JP2002506061A - 1,2-Diazepan derivatives as inhibitors of interleukin-1β converting enzyme - Google Patents

Abstract

(57) SUMMARY The present invention relates to caspase inhibitors, particularly interleukin-1β converting enzymes (“ICE”) represented by formula (I), wherein Y is (a) or (b). A new class of compounds that are inhibitors of The present invention also provides methods of inhibiting caspase activity, and methods of reducing the production of IGIF and IFN-γ using the compounds and compositions of the invention, and interleukin-1, apoptosis and interleukin-γ And a method of treating a disease mediated by the disease. The present invention also relates to a method for preparing a compound of the present invention. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD OF THE INVENTION The present invention relates to caspase inhibitors, particularly interleukin-1β converting enzymes (
"ICE"), a new class of compounds. The present invention also relates to pharmaceutical compositions containing these compounds. The compounds and pharmaceutical compositions of the present invention are particularly well-suited for inhibiting caspase activity, and as a result, interleukin-1 ("IL-1"), apoptosis, interferon-γ inducer (IGIF), Alternatively, it is advantageously used as a drug for diseases mediated by interferon-γ (“IFN-γ”), including inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases and degenerative diseases Can be done. The present invention also provides methods of inhibiting caspase activity and reducing IGIF and IFN-γ production, and mediated by interleukin-1, apoptosis and interferon-γ, using compounds and compositions of the invention. A method of treating a disease. The present invention also relates to a method for preparing a compound of the present invention.

BACKGROUND OF THE INVENTION [0002] Interleukin-1 ("IL-1") is responsible for fibroblast differentiation and proliferation, production of prostaglandins, collagenases and phospholipases by synovial cells and chondrocytes, basophils and It is a major proinflammatory and immunomodulatory protein that stimulates eosinophil degranulation as well as neutrophil activation. Oppenheim, J. et al. H. Et al., Immunology Toda
y, 7, 45-56 (1986). Thus, it is involved in the pathogenesis of chronic and acute inflammatory diseases as well as autoimmune diseases. For example, in rheumatoid arthritis, IL-1 is both a mediator of inflammatory symptoms and a mediator of cartilage proteoglycan destruction in affected joints. Wood, D.C.
D. Et al., Arthritis Rheum. , 26, p. 975 (1983);
ettipher, E .; J. Proc. Natl. Acad. Sci. U
SA, 71, 295 (1986); P. And Dayer,
J. M. Arthritis Rheum. 38, 151 (1995).
IL-1 is also a very powerful bone resorbent. Jandski, J .;
J. J. Oral Path. , 17, 145 (1988); Dewhir.
st, F. E. FIG. J. et al. Immunol. , 8, 2562 (1985). It is also called "osteoclast activator" in destructive bone diseases such as osteoarthritis and multiple myeloma. Bataille, R .; Et al., Int. J. Clin
. Lab. Res. , 21 (4), p. 283 (1992). In certain proliferative disorders, such as acute myeloid leukemia and multiple myeloma, IL-1 may promote tumor cell proliferation and adhesion. Bani, M .; R. J. Natl. Canc
er Inst. 83, 123 (1991); Vidal-Vanaclo.
cha, F.C. , Cancer Res. , 54, 2667 (1994). In these disorders, IL-1 also stimulates the production of other cytokines, such as IL-6, which can regulate tumor development (Tartour et al., Cancer R).
es. , 54, 6243 (1994)). As part of the inflammatory response, IL-1 is mainly produced by peripheral blood monocytes and has two distinct agonist forms (IL-
1α and IL-1β). See Mosley, B .; S. Proc. N
at. Acad. Sci. , 84, 4572-4576 (1987); Lon.
nemann, G .; Et al., Eur. J. Immunol. , 19, 1531-15
36 (1989).

[0003] IL-1β is synthesized as pIL-1β, a biologically inactive precursor. pIL-1β lacks a conventional leader sequence and is not processed by signal peptidases. March, C.M. J. , Nature, 315,
641-647 (1985). Instead, pIL-1β becomes Asp-116
Is cleaved between and Ala-117 by interleukin-1β converting enzyme (“ICE”) to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleep, P.M. R. J. et al. Biol. Chem. , 2
65, 14526-14528 (1992); Howard, A .; D. J
. Immunol. , 147, 2964-2969 (1991). ICE is
Cysteine protease mainly located on monocytes. This is the precursor IL-1β
To the mature form. Black, R.A. A. Et al., FEBS Lett. , 24
7, 386-390 (1989); Kosuta, M .; J. Proc.
Natl. Acad. Sci. U. S. A. , 86, 5227-5231 (1
989). Processing by ICE also results in mature IL-1β through the cell membrane.
Required for transportation.

[0004] ICE is a member of a family of homologous enzymes called caspases.
These homologs have sequence similarity in the region of the active site of the enzyme. Such homologs (caspases) include TX (or ICE _rel-II or ICH).
-Z) (Faucheu et al., EMBO J., 14, 1914 (1995);
Kamens J. et al. J. et al. Biol. Chem. 270, 15250 pages (1
995); Nicholson et al. Biol. Chem. , 270 158
70 (1995)), TY (or ICE _rel-III ) (Nicholson et al., J. Biol. Chem., 270 15870 (1995); ICH-1 (
Or Nedd-2) (Wang, L. et al., Cell, 78, 739 (199).
4)), MCH-2, (Fernandes-Alnemri, T. et al., Can.
cer Res. 55, 2737 (1995), CPP32 (or YAM).
A or apopain) (Fernandes-Alnemri, T. et al., J. Am.
Biol. Chem. 269, 30761 (1994); Nicholso
n, D. W. Et al., Nature, 376, p. 37 (1995)), and CM
H-1 (or MCH-3) (Lippke et al., J. Biol. Chem., (
1996); Fernandez-Alnemri, T .; Et al., Cancer R
es. , (1995)).

[0005] Each of these ICE homologs, and ICE itself, can induce apoptosis when overexpressed in transfected cell lines. Peptidyl IC
Inhibition of one or more of these homologs with the E inhibitor Tyr-Val-Ala-Asp-chloromethylketone results in inhibition of apoptosis in progenitor cells or cell lines. Lazebnik et al., Nature, 371, 346 (1994).

[0006] Caspases also appear to be involved in the regulation of programmed cell death or apoptosis. Yuan, J. et al., Cell, 75, 641-652 (199).
3); Miura, M et al., Cell, 75, 653-660 (1993);
ett-Fiordalisi, M .; A. J. et al. Cell Biochem.
, 17B, p. 117 (1993). In particular, ICE or ICE homologs are thought to be involved in the regulation of apoptosis in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Marx, J .; And Baringa, M
. , Science, 259, pp. 760-762 (1993); Gagliar.
dini, V .; Et al., Science, 263, 826-828 (1994).
Therapeutic applications for inhibition of apoptosis can include treatment of Alzheimer's disease, Parkinson's disease, stroke, myocardial infarction, spinal cord atrophy and aging.

[0007] ICE has been demonstrated to mediate apoptosis (programmed cell death) in certain tissue types. Steller, H .; , Science, 26
7, 1445 (1995); Whyte, M .; And Evan, G .; , Nat
ure, 376, 17 (1995); Martin, S .; J. And Green
n, D. R. , Cell, 82, 349 (1995);
S. J. et al. Biol. Chem. 270, 4312 (1995); Yua.
n, J. et al. Curr. Opin. Cell Biol. , 7, 211 (1995)
). Transgenic mice with a disrupted ICE gene are defective in Fas-mediated apoptosis (Kuida, K. et al., Science, 267, 2).
000 (1995)). This activity of ICE is distinguished from its role as a processing enzyme for pro-IL-1β. In certain tissue types, inhibition of ICE may not affect the secretion of mature IL-1β, but may be able to inhibit apoptosis.

[0008] Enzymatically active ICE has previously been described as a heterodimer consisting of two subunits, p20 and p10 (molecular weights 20 kDa and 10 kDa, respectively). These subunits are derived from the 45 kDa proenzyme (p45) via the p30 form via an activation mechanism that is autocatalytic. Thorn
berry, N.M. A. Et al., Nature, 356, 768-774 (1992).
). The ICE proenzyme has been divided into several functional domains: prodomain (p14), p22 / 20 subunit, polypeptide linker and p10 subunit. Thornberry et al., Supra; Casano et al., Gen.
omics, 20, 474-481 (1994).

[0009] Full-length p45 has been characterized by its cDNA and amino acid sequences. P
CT Patent Applications WO 91/15577 and WO 94/00154. The cDNA and amino acid sequences of p20 and p10 are also known. Th
ornberry et al., supra. Mouse and rat ICE have also been sequenced,
And it has been cloned. They have high amino acid and nucleic acid sequence homology to human ICE. Miller, D.M. K. Et al., Ann. N. Y. Ac
ad. Sci. , 696, 133-148 (1993); Molineaux.
, S .; M. Proc. Nat. Acad. Sci. , 90, 1809-18
Page 13 (1993). The three-dimensional structure of ICE has been determined by atomic analysis by X-ray crystallography. Wilson, K .; P. Et al., Nature, 370, 270-27.
5 (1994). The active enzyme exists as a tetramer of two p20 and two p10 subunits.

In recent years, ICE and other members of the ICE / CED-3 family have been
It has been implicated in the conversion of GIF to IGIF or in the production of IFN-γ in vivo. (PCT application PCT / US96 / 20843 (12/20/96 application, published application number WO 97/22619, 6/26/97, which is incorporated herein by reference).) IGIF is a precursor Protein "Pro-IGIF
And synthesized in vivo.

[0011] Interferon-γ inducer (IGIF) is an interferon-γ (IFIF)
N-γ) is an approximately 18-kDa polypeptide that stimulates T cell production. IGI
F is produced in vivo by activated Kupffer cells and macrophages and is exported out of such cells upon endotoxin stimulation. Therefore,
Compounds that reduce IGIF production are useful as inhibitors of such T cell stimulation, which in turn reduces the level of IFN-γ production by these cells.

[0012] IFN-γ is a cytokine having an immunomodulatory effect on various immune cells. In particular, IFN-γ is involved in macrophage activation and Th1 cell selection (F. Belardelli, APMIS, 103, 161 (199).
5)). IFN-γ exerts its effects, in part, by regulating gene expression via the STAT and IRF pathways (C. Schindler, and J.
. E. FIG. Darnell, Ann. Rev .. Biochem. , 64, 621 (
1995); Taniguchi, J .; Cancer. Res. Clin.
Oncol. , 121, 516 (1995)).

Mice deficient in IFN-γ or its receptor have multiple defects in immune cell function and are resistant to endotoxin shock (S. Huang et al., Science, 259,
1742 (1993); Dalton, et al., Science, 259, 1
739 (1993); D. Car. J. et al. Exp. Med. , 179,
1437 (1994)). IGIF, together with IL-12, is used to
It appears to be a strong inducer of N-γ production (H. Okamura et al.,
Infection and Immunity, 63, 3966 (1995)
H.); Okamura et al., Nature, 378, p. 88 (1995);
Ushio et al. Immunol. 156, 4274 (1996)).

[0014] IFN-γ has been shown to contribute to pathologies associated with various inflammatory, infectious, and autoimmune disorders and diseases. Thus, compounds that can reduce IFN-γ production are useful for ameliorating the effects of IFN-γ related conditions.

Thus, compositions and methods that can modulate the conversion of pro-IGIF to IGIF include:
It is useful for reducing IGIF and IFN-γ production in vivo and is therefore useful for ameliorating the deleterious effects of these proteins that contribute to human disorders and diseases.

[0016] Caspase inhibitors represent a class of compounds useful for controlling inflammation and / or apoptosis. ICE peptides and peptidyl inhibitors have been described. PCT Patent Application No. WO 91/15577;
No. 93/05071; WO 93/09135; WO 93/147
77 and WO 93/16710; and European Patent Application No. 0 547 699. Such peptidyl inhibitors of ICE have been observed to block production of mature IL-1β in a mouse model of inflammation (see below) and to suppress leukemic cell growth in vitro (Estr
ov et al., Blood 84, 380a (1994)). However, due to their peptidic nature, such inhibitors typically have undesirable pharmacological properties such as poor cell penetration and cell activity, poor oral absorption, poor stability and rapid metabolism. Is characterized by Plattner, J .;
J. And D. W. Norbeck, Drug Discovery Tech
noologies, C.I. R. Clark, and W.C. H. Moos, Hen (El
lis Horwood, Chichester, England, 1990)
, 92-126. This has hindered the development of effective drugs.

Non-peptidyl compounds have also been reported to inhibit ICE in vitro. PCT Patent Application No. WO 95/26958; US Pat. No. 5,552,4
No. 00; Dolle et al. Med. Chem. , 39, 2438-2440 (1996). However, it is not clear whether these compounds have appropriate therapeutically useful pharmacological properties.

Thus, chronic and acute forms of IL-1-mediated disease, apoptosis, IGIF,
Or caspases for use as agents to prevent and treat IFN-γ mediated diseases, as well as inflammatory, autoimmune, destructive bone, proliferative, infectious, or degenerative diseases. There is a need for compounds that can inhibit.

SUMMARY OF THE INVENTION The present invention provides a novel class of compounds useful as inhibitors of caspases, especially as ICE inhibitors, and their pharmaceutically acceptable derivatives. These compounds, alone or in combination with other therapeutic or prophylactic agents (eg, antibiotics, immunomodulators or other anti-inflammatory agents), mediate IL-1, apoptosis, IGIF or IFN-γ. It can be used for the treatment or prevention of diseases that occur. According to a preferred embodiment, the compounds of the invention are capable of binding to the active site of ICE and inhibiting the activity of the enzyme.

The main object of the present invention is to provide a new class of compounds represented by the formula:

[0021]

Embedded image Here, various substituents are described in the present specification.

The present invention also provides compositions comprising the compounds represented by formulas (I) and (II), methods of using these compositions in treating or preventing various disorders, and methods of preparing these compounds. provide.

DETAILED DESCRIPTION OF THE INVENTION In order that the invention described herein may be more fully understood, the following detailed description is set forth.

The following abbreviations and definitions are used throughout the application.

(Abbreviations) Ac ₂ O Acetic anhydride n-Bu normal-butyl DMF dimethylformamide DIEA N, N-diisopropylethylamine EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et ₂ O diethyl ether EtOAc Ethyl acetate Fmoc 9-Fluorenylmethyloxycarbonyl HBTU O-benzotriazol-1-yl-N, N, N, N'-tetramethyluronium hexafluorophosphate HOBT 1-hydroxybenzotriazole hydrate MeOH methanol TFA tri Fluoroacetate The term “caspase” refers to an enzyme that is a member of a family of enzymes including ICE (H. Hara, Natl. Acad. Sci., 94, 2007-2).
012 (1997)).

The terms “HBV”, “HCV” and “HGV” refer to hepatitis B virus, hepatitis C virus and hepatitis G virus, respectively.

The term “K _i ” refers to a numerical measure of the effectiveness of a compound of inhibiting the activity of a target enzyme (eg, ICE). The value K _i of less reflects the high efficacy. This Ki value is derived by fitting experimentally determined rate data to standard enzyme rate equations (IH Segel, Enzyme Kinet).
ics, Wiley-Interscience, 1975).

The term “interferon-γ inducer” or “IGIF” refers to IFN-γ
Refers to factors that can stimulate endogenous production of

The term “caspase inhibitor” refers to a compound that can exhibit detectable inhibition of one or more caspases. The term "ICE inhibitor" refers to a compound that can exhibit detectable inhibition of ICE and, optionally, one or more additional caspases. Inhibition of these enzymes can be measured using the methods described herein and incorporated by reference. One skilled in the art will recognize that in vivo enzyme inhibitors
Understand that it is not an in vitro enzyme inhibitor. For example, compounds in prodrug form typically exhibit little or no activity in in vitro assays. Such prodrug forms can be modified by metabolic or other biochemical processes within the patient to provide an in vivo enzyme inhibitor.

The term “cytokine” refers to a molecule that mediates interactions between cells.

The term “condition” refers to any disease, disorder or effect that produces a deleterious biological result in a subject.

The term “subject” refers to an animal, or one or more cells derived from an animal. Preferably, the animal is a mammal, most preferably, a human. Cells can take any form, including cells retained in tissues, cell clusters, immortalized cells, transfected or transformed cells, and cells from animals that have been physically or phenotypically altered. But not limited thereto.

As used herein, the term “patient” refers to any mammal, preferably a human.

The term “alkyl” refers to a straight or branched chain saturated aliphatic hydrocarbon containing 1-6 carbons.

The term “alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 6 carbon atoms and at least one double bond.

The term “alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 6 carbon atoms and at least one triple bond.

The term “cycloalkyl” refers to a mono- or polycyclic non-aromatic hydrocarbon ring system, which may optionally include unsaturated bonds within the ring system. Examples include:
Cyclohexyl, adamantyl and norbornyl.

The term “aryl” refers to a monocyclic or polycyclic ring system containing 6, 10, 12, or 14 carbons, wherein at least one ring of the ring system is aromatic. A person who is a tribe. The aryl group of the present invention is optionally substituted singly or plurally by R ¹⁷ . Examples of aryl ring systems include phenyl, naphthyl and tetrahydronaphthyl.

The term “heteroaryl” refers to a monocyclic or polycyclic ring system containing 1 to 15 carbon atoms and 1 to 4 heteroatoms, wherein at least one of the ring systems One ring is aromatic. Heteroatoms are sulfur, nitrogen or oxygen. The heteroaryl groups of this invention can optionally be one or more substituted with R ^17.

The term “heterocyclic” refers to a monocyclic or polycyclic ring system containing 1 to 15 carbon atoms and 1 to 4 heteroatoms, the monocyclic or polycyclic ring system. Cyclic ring systems may optionally include unsaturated bonds but are not aromatic. Heteroatoms are independently sulfur, nitrogen or oxygen.

The term “alkylaryl” refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with one or more aryl radicals.

The term “alkylheteroaryl” refers to an alkyl group wherein a hydrogen atom of the alkyl group has been replaced with a heteroaryl radical.

The term “substituted” means to replace a hydrogen atom in a compound with a substituent.

The term “straight chain” means a continuous, unbranched string of covalently bonded atoms. The straight chain can be substituted, but the substituents are not part of the straight chain.

The term “amino acid side chain” refers to a substituent attached to the α-carbon of either a natural α-amino acid or a non-natural α-amino acid.

In chemical formulas, parentheses are used herein to indicate the connectivity of a molecule or group. In particular, parentheses are used to indicate: 1) that more than one atom or group is attached to a particular atom; 2) the branch point (ie, the atom immediately before the opening bracket is Attached to both the atom or group in parentheses and the atom or group immediately following the closing parenthesis). One example of a first use is "-N (alkyl) _2, " which indicates two alkyl groups attached to an N atom. An example of a second use, "- C (O) NH _2" has, which is instructed together bound carbonyl group and an amino carbon atoms ( "NH _2") indicates the group. A “—C (O) NH ₂ ” group may be represented in other manners, including the following structures:

[0047]

Embedded image Substitutes may be presented in various forms. These various forms are known to those skilled in the art and may be used interchangeably. For example, a methyl substituent on a phenyl ring can be represented in any of the following forms:

[0048]

Embedded image Various forms of substituents, such as methyl, are used interchangeably herein.

Other definitions are set forth herein, where necessary.

Compound of the Invention The compound of one embodiment (A) of the present invention is a compound of formula (I):

[0051]

Embedded image Where: Y is:

[0052]

Embedded image Provided that when R ⁵ is -OH, Y may also be located in the following:

[0053]

Embedded image m is 0 or 1; W _{is, -CH 2 -, - C (} O) -, S (O) 2 or -S, (O) - is; X is -C (H) -, —C (R ⁸ ) —, or

[0054]

Embedded image Z is —CH ₂ —, —O—, —S—, or —N (R ¹ ) — (provided that if Z is —N (R ¹ ) —, then W is —C (O)-, -S (O) _2- , or -S (O
) - if it is); each R ¹ is independently, -H, -C (O) R 8, -S (O) 2 R 8, -S (O) R 8, -R 21, - alkyl - R ²¹ , -alkenyl-R ²¹ , or -alkynyl-R ²¹ ; R ² is —C (O) R ⁸ , —C (O) C (O) R ⁸ , —S (O) ₂ R ^{8 , -S (O) R 8,} -C (O) OR 8, -C (O) N (H) R 8, -S (O) 2 N (H) -R 8, -S (O) N ( ^{H) -R 8, -C (O} ) C (O) N (H) R 8, -C (O) CH
^{= CHR 8, -C (O)} CH 2 OR 8, -C (O) CH 2 N (H) R 8, -C (O) N (R 8) 2, -S (O) 2 N (R 8 ) ₂ , -S (O) N (R ⁸ ) ₂ , -C (O) C (O) N (R ⁸ ) ₂ , -C (O) CH ₂ N (R ⁸ ) ₂ , -CH ₂ -R ^8, -CH ₂ - alkenyl -R ⁸ or -CH _2, - there alkynyl -R ^8; R ³ is, -H, -R ^21, - alkyl -R ^21, - alkenyl -R ^21, or - A Rukiniru It is -R ^21; each R ⁴ is independently, -OH, -F, -Cl, -Br , -I, -NO 2, -CN
_{, -NH 2, -CO 2 H,} -C (O) NH 2, -N (H) C (O) H, -N (H) C (O) NH 2, - alkyl, - cycloalkyl, - Par Fluoroalkyl, -O-alkyl, -N (H) alkyl, -N (alkyl) ₂ , -C (O) N (H) alkyl, -C (O) N (alkyl) ₂ , -N (H) C (O) alkyl, -N (H) C (O ) N (H) alkyl, -N (H) C (O ) N ( alkyl) _2, -S- alkyl, -S (O) ₂ alkyl, -S is N (H) C (O) O -alkyl - (O) alkyl, -C (O) _{alkyl, -CH 2 NH 2, -CH 2} N (H) alkyl, -CH ₂ N (alkyl) ₂ or, ; R ⁵ is, -OH, is -OR ⁸ or -N (H) OH; R ^{6 _{is, -H, -CH 2 oR 9,}} -CH 2 SR 10, -CH 2 N (H) R 9 Is ^{_{-CH 2 N (R 9) R}} 11, -C (H) N 2, -CH 2 F, -CH 2 Cl, -C (O) N (R 11) 2, -R 13 or -R ¹⁴ Each R ⁸ is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocycle, -alkylcycloalkyl, -alkylaryl, -alkylheteroaryl, or -alkylheterocycle; R ⁹ is, -H, -C (O) aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (O) alkylheteroaryl, - alkylaryl,
-Alkylheteroaryl, -aryl, heteroaryl, or -P (O) (
Is R ¹⁵⁾ _2; R ¹⁰ is - alkylaryl or - is an alkyl heteroaryl; each R ¹¹ is independently, -H, - alkyl, - aryl, - heteroaryl, -
R ¹³ is -alkylaryl or -alkylheteroaryl; R ¹⁴ is:

[0055]

Embedded image Here, Q is -O- or -S-, any hydrogen atom in (i) is optionally is substituted with -R ^17, and (ii), (iii), and Any hydrogen atom in (iv) may be -R ¹⁷ , -R ¹⁸ or-
It is the substituted alkyl -R ^18; each R ¹⁵ is independently, -H, -OH, - alkyl, - aryl, - heteroaryl, - cycloalkyl, - alkylaryl, - alkylheteroaryl, -
O-alkyl, is -O aryl, -O heteroaryl, -O alkylaryl or -O-alkyl heteroaryl; each R ¹⁷ is independently, -OH, -F, -Cl, -Br, -I, _{-NO 2, -C N, -NH 2} , -CO 2 H, -C (O) NH 2, -N (H) C (O) H, -N (H) C (O) NH 2, -SO _{2 NH 2, -C (O)} H, - alkyl, - cycloalkyl Le - perfluoroalkyl, -O- alkyl, -N (H) alkyl, -N (alkyl) _2, -CO ₂ alkyl, -C ( O) N (H) alkyl, -C (O) N (alkyl) ₂ , -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H ) C (O) N _{(alkyl) 2, -S (O) 2} N (H) alkyl, -S
(O) N (H) alkyl, -S (O) ₂ N _{(alkyl) 2, -S (O) N} ( alkyl) _2, -S- alkyl, -S (O) ₂ alkyl, -S (O) Alkyl, or-
Each R ¹⁸ is independently -aryl, -heteroaryl, -alkylaryl,
-Alkylheteroaryl, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O-alkylheteroaryl, -N (H) aryl, -N (
Aryl) ₂ , -N (H) heteroaryl, -N (heteroaryl) ₂ , -N (H
) Alkylaryl, -N (alkylaryl) ₂ , -N (H) alkylheteroaryl, -N (alkylheteroaryl) ₂ , -S-aryl, -S-heteroaryl, -S-alkylaryl, -S- Alkylheteroaryl, -C (O
) Aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (
O) alkylheteroaryl, -CO ₂ aryl, -CO ₂ heteroaryl, -C
O ₂ alkylaryl, -CO ₂ alkylheteroaryl, -C (O) N (H) aryl, -C (O) N (aryl) _2, -C (O) N (H) heteroaryl, - C (O ) N (heteroaryl) ₂ , -C (O) N (H) alkylaryl, -C (O) N (alkylaryl) ₂ , -C (O) N (H) alkylheteroaryl, -C (O) N (alkylheteroaryl) ₂ , —S (O) ₂ -aryl, —S (
O) -aryl, -S (O) ₂ -heteroaryl, -S (O) -heteroaryl, -S (O) _2- alkylaryl, -S (O) -alkylaryl, -S (O) _2- alkylheteroaryl, -S (O) - alkyl _{heteroaryl, -S (O) 2 N (} H) - aryl, -S (O) N (H ) - aryl, -S (O) ₂ NH-
Heteroaryl, -S (O) NH- _{heteroaryl, -S (O) 2 N (} H) - A Rukiruariru, S (O) N (H ) - _{alkylaryl, -S (O) 2 N (} H) - Alkylheteroaryl, -S (O) N (H) -alkylheteroaryl,-
S (O) ₂ N _{(aryl) 2, -S (O) N} ( _{aryl) 2, -S (O) 2} N ( _{heteroaryl) 2, -S (O) N} ( heteroaryl) _2, -S ( O) ₂ N (alkylaryl) _2, -S (O) N (alkyl aryl) _2, -S (O) ₂ N (alkylheteroaryl) _2, -S (O) N (alkyl heteroaryl) _2, - N (H) C
(O) N (H) aryl, -N (H) C (O) N (H) heteroaryl, -N (
H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) alkylheteroaryl, -N (H) C (O) N (aryl) ₂ , -N (H) C (O) N (heteroaryl) ₂ , -N (H) C (O) N (alkylaryl) ₂ , or-
N (H) C (O) N (alkylheteroaryl) ₂ ; R ¹⁹ is hydrogen; and each R ²¹ is independently -aryl, -heteroaryl, -cycloalkyl, or -hetero. Wherein the hydrogen atom attached to any carbon atom is optionally substituted with R ⁴ , and the hydrogen atom attached to any nitrogen atom is optionally substituted with R ² Is replaced by

A compound of another embodiment (B) of the present invention is a compound of formula (II):

[0057]

Embedded image Here: C is an aryl or heteroaryl ring, wherein any hydrogen atoms bonded to the C ring is optionally substituted with -R ^4; and the other substituents, embodiments ( In A) is the same as described above.

The compounds of two other embodiments (C) and (D) of the present invention each have the formula (
A compound of I) or (II), wherein: Y is (c), (d), (e) or (f), and R ¹⁹ is hydrogen:

[0059]

Embedded image And when R ¹⁹ is not hydrogen, R ¹⁹ and Y together with the nitrogen atom to which they are attached form a ring (g);

[0060]

Embedded image R ⁷ is, -C (O) alkyl, -C (O) cycloalkyl, -C (O) alkenyl, -C (O) alkynyl, -C (O) alkylaryl, -C (O) alkylheteroaryl is the -C (O) heterocycle, or -C (O) alkyl heterocycle; each R ²² is independently, -H, - alkyl, - aryl, - heteroaryl, -
And cycloalkyl, -alkylaryl, or -alkylheteroaryl; and the other substituents are the same as those described above.

Preferably: m is O; W is —CH ₂ — or —C (O) —;

[0062]

Embedded image Z is a --CH2 -; R ⁵ is a -OH; R ⁶ is -H or -R ^14; R ⁷ is a -C (O) alkyl; R ⁸ is methyl, Ethyl, n-propyl, isopropyl, cyclopentyl, phenethyl, or benzyl; or R ⁹ is —C (O) aryl, —C (O) heteroaryl, —C (O) alkylaryl, —C (O) alkyl heteroaryl, - alkylaryl, - heteroaryl alkylheteroaryl, - - aryl or; or R ¹⁴ is substituted with (i) -O-alkyl, -F or -Cl,; Q is located in O Or (ii) substituted with phenyl; or C is a benzo ring, wherein any hydrogen atom attached to the ring is optionally substituted with -R ⁴ ; more preferably, R ⁶ Is hydrogen .

In any of the above embodiments, preferred forms of formula (i) are:

[0064]

Embedded image

[0065]

Embedded image And the other substituents are the same as those described above.

In any of the above embodiments, preferred forms of formula (ii) are:

[0067]

Embedded image C is a benzo ring, wherein any hydrogen atoms bonded to the ring is substituted with -R ⁴ as necessary;

[0068]

Embedded image And the other substituents are the same as those described above.

The compound of preferred embodiment (E) of the present invention is a compound of formula (I):

[0070]

Embedded image

[0071]

Embedded image Each R ¹ is independently -H, -C (O) R ⁸ , -S (O) ₂ R ⁸ , -S (O) R ⁸ , -R ²¹ , -alkyl-R ²¹ , -alkenyl- R ^{21 is} -alkynyl-R ²¹ -alkyl; R ² is -C (O) R ⁸ , -C (O) C (O) R ⁸ , -S (O) ₂ R ⁸ , -S ( ^{O) R 8, -C (O} ) OR 8, -C (O) N (H) R 8, -S (O) 2 N (H) -R 8, -S (O) N (H) -R ^{8, -C (O) C (} O) N (H) R 8, -C (O) CH
^{= CHR 8, -C (O)} CH 2 OR 8, -C (O) CH 2 N (H) R 8, -C (O) N (R 8) 2, -S (O) 2 N (R 8 ) ₂ , -S (O) N (R ⁸ ) ₂ , -C (O) C (O) N (R ⁸ ) ₂ , -C (O) CH ₂ N (R ⁸ ) ₂ , -CH ₂ -R ^8, -CH ₂ - alkenyl -R ⁸ or -CH _2, - there alkynyl -R ^8; R ³ is, -H, -R ^21, - alkyl -R ^21, - alkenyl -R ^21, - Arukini Le - R ²¹ , alkyl, or an amino acid side chain; each R ⁴ is independently —OH, —F, —Cl, —Br, —I, —NO ₂ , —CN
_{, -NH 2, -CO 2 H,} -C (O) NH 2, -N (H) C (O) H, -N (H) C (O) NH 2, - alkyl, - cycloalkyl, - Par Fluoroalkyl, -O-alkyl, -N (H) alkyl, -N (alkyl) ₂ , -C (O) N (H) alkyl, -C (O) N (alkyl) ₂ , -N (H) C (O) alkyl, -N (H) C (O ) N (H) alkyl, -N (H) C (O ) N ( alkyl) _2, -S- alkyl, -S (O) ₂ alkyl, -S is N (H) C (O) O -alkyl - (O) alkyl, -C (O) _{alkyl, -CH 2 NH 2, -CH 2} N (H) alkyl, -CH ₂ N (alkyl) ₂ or, ; R ⁵ is, -OH, is -OR ^8, -N (H) OH or ^{_{-N (H) SO 2 R 8}} ; R 6 ^{_{is, -H, -CH 2 oR 9,}} -CH 2 SR 10 ^{_{-CH 2 N (H) R 9}} , -CH 2 N (R 9) R 11, -C (H) N 2, -CH 2 F, -CH 2 Cl, -CH 2 Br, -C H 2 I, ^{-C (O) N (R 11} ) 2, is -R ¹³ or -R ^14,; each R ⁸ is independently - alkyl, - cycloalkyl, - aryl, - heteroaryl, - heterocycle, - alkylcycloalkyl, - alkylaryl, - alkylheteroaryl or, - alkyl is heterocycle; R ⁹ is, -H, -C (O) aryl, -C (O) heteroaryl, -C (O) alkyl Aryl, -C (O) alkylheteroaryl, -alkylaryl,
-Alkylheteroaryl, -aryl, heteroaryl, or -P (O) (
Is R ¹⁵⁾ _2; R ¹⁰ is - alkylaryl or - is an alkyl heteroaryl; each R ¹¹ is independently, -H, - alkyl, - aryl, - heteroaryl, -
R ¹³ is -alkylaryl or -alkylheteroaryl; R ¹⁴ is:

[0072]

Embedded image Here, Q is -O- or -S-, any hydrogen atom in (i) is optionally is substituted with -R ^17, and (ii), (iii), and Any hydrogen atom in (iv) may be -R ¹⁷ , -R ¹⁸ or-
It is the substituted alkyl -R ^18; each R ¹⁵ is independently, -H, -OH, - alkyl, - aryl, - heteroaryl, - cycloalkyl, - alkylaryl, - alkylheteroaryl, -
O-alkyl, is -O aryl, -O heteroaryl, -O alkylaryl or -O-alkyl heteroaryl; each R ¹⁷ is independently, -OH, -F, -Cl, -Br, -I, _{-NO 2, -C N, -NH 2} , -CO 2 H, -C (O) NH 2, -N (H) C (O) H, -N (H) C (O) NH 2, -SO _{2 NH 2, -C (O)} H, - alkyl, - cycloalkyl Le - perfluoroalkyl, -O- alkyl, -N (H) alkyl, -N (alkyl) _2, -CO ₂ alkyl, -C ( O) N (H) alkyl, -C (O) N (alkyl) ₂ , -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H ) C (O) N _{(alkyl) 2, -S (O) 2} N (H) alkyl, -S
(O) N (H) alkyl, -S (O) ₂ N _{(alkyl) 2, -S (O) N} ( alkyl) _2, -S- alkyl, -S (O) ₂ alkyl, -S (O) Alkyl, or-
Each R ¹⁸ is independently -aryl, -heteroaryl, -alkylaryl,
-Alkylheteroaryl, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O-alkylheteroaryl, -N (H) aryl, -N (
Aryl) ₂ , -N (H) heteroaryl, -N (heteroaryl) ₂ , -N (H
) Alkylaryl, -N (alkylaryl) ₂ , -N (H) alkylheteroaryl, -N (alkylheteroaryl) ₂ , -S-aryl, -S-heteroaryl, -S-alkylaryl, -S- Alkylheteroaryl, -C (O
) Aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (
O) alkylheteroaryl, -CO ₂ aryl, -CO ₂ heteroaryl, -C
O ₂ alkylaryl, -CO ₂ alkylheteroaryl, -C (O) N (H) aryl, -C (O) N (aryl) _2, -C (O) N (H) heteroaryl, - C (O ) N (heteroaryl) ₂ , -C (O) N (H) alkylaryl, -C (O) N (alkylaryl) ₂ , -C (O) N (H) alkylheteroaryl, -C (O) N (alkylheteroaryl) ₂ , —S (O) ₂ -aryl, —S (
O) -aryl, -S (O) ₂ -heteroaryl, -S (O) -heteroaryl, -S (O) _2- alkylaryl, -S (O) -alkylaryl, -S (O) _2- alkylheteroaryl, -S (O) - alkyl _{heteroaryl, -S (O) 2 N (} H) - aryl, -S (O) N (H ) - aryl, -S (O) ₂ NH-
Heteroaryl, -S (O) NH- _{heteroaryl, -S (O) 2 N (} H) - A Rukiruariru, S (O) N (H ) - _{alkylaryl, -S (O) 2 N (} H) - Alkylheteroaryl, -S (O) N (H) -alkylheteroaryl,-
S (O) ₂ N _{(aryl) 2, -S (O) N} ( _{aryl) 2, -S (O) 2} N ( _{heteroaryl) 2, -S (O) N} ( heteroaryl) _2, -S ( O) ₂ N (alkylaryl) _2, -S (O) N (alkyl aryl) _2, -S (O) ₂ N (alkylheteroaryl) _2, -S (O) N (alkyl heteroaryl) _2, - N (H) C
(O) N (H) aryl, -N (H) C (O) N (H) heteroaryl, -N (
H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) alkylheteroaryl, -N (H) C (O) N (aryl) ₂ , -N (H) C (O) N (heteroaryl) ₂ , -N (H) C (O) N (alkylaryl) ₂ , or-
N (H) C (O) N (alkylheteroaryl) ₂ ; and each R ²¹ is independently -aryl, -heteroaryl, cycloalkyl, or -heterocycle, wherein any carbon hydrogen atom attached to the atom is optionally is substituted with R ^4, and hydrogen atom attached to any nitrogen atom is optionally substituted with R ^2.

A compound of another preferred embodiment (F) of the present invention is a compound of formula (II):

[0074]

Embedded image Here: C is an aryl or heteroaryl ring, wherein any hydrogen atoms bonded to the C ring is optionally is substituted by -R ^4; and the other substituents, exemplary Same as described above in embodiment (E).

The compounds of two other embodiments (G) and (H) of the present invention each have the formula (
A compound of I) or (II), wherein: Y is (c), (d), (e), or (f):

[0076]

Embedded image R ⁷ is, -C (O) alkyl, -C (O) cycloalkyl, -C (O) alkenyl, -C (O) alkynyl, -C (O) alkylaryl, -C (O) alkylheteroaryl , -C (O) heterocycle, or -C (O) alkylheterocycle; and the other substituents are as shown above, preferably: m is 0; W is -CH _2- or -C (O)-;

[0077]

Embedded image Z is -CH ₂ - and is; R ⁵ is -OH; R ⁶ is -H, -R ^14, be -CH ₂ OR ⁹ or -CH ₂ F; R ⁷ is, -C ( R ⁸ is methyl, ethyl, n-propyl, isopropyl, cyclopentyl, phenethyl or benzyl; R ⁹ is —C (O) aryl, —C (O) heteroaryl, C (O) alkyl Ruariru, -C (O) alkylheteroaryl, - alkylaryl, - alkylheteroaryl, - aryl or - heteroaryl; Q is an O; R ¹⁴ is (i) - O alkyl, -F or -Cl, or (i
i) substituted with phenyl; C is a benzene ring, wherein any hydrogen bond to the ring is substituted with -R ⁴ as necessary; R ¹ is aryl, heteroaryl, alkyl, Is alkylaryl, or alkylheteroaryl; or R ³ is an amino acid side chain, aryl, heteroaryl, alkyl, alkylaryl, or alkylheteroaryl.

More preferably, R ¹ is:

[0079]

Embedded image R ² is:

[0080]

Embedded image R ³ is:

[0081]

Embedded image Or R ⁶ is —H.

In embodiments (C), (D), (G), or (H), Y is:

[0083]

Embedded image And V is preferably:

[0084]

Embedded image It is.

In any of the above embodiments, preferred forms of formula (I) include the following: Z is -CH _2- , W is -C (O)-, and X is -C (H)-(Ia Z is —CH ₂ —, W is —CH ₂ —, and X is —C (H) — (Ib);

[0086]

Embedded image

[0087]

Embedded image And the other substituents are as described above.

A more preferred form of formula (I) is:

[0089]

Embedded image It is.

In any of the above embodiments, preferred forms of formula (II) are: wherein W is —C (O) — and X is —C (H) — (IIa); —CH ₂ — and X is —C (H) — (IIb);

[0091]

Embedded image And C is a benzene ring, wherein any hydrogen bond bonded to this ring is optionally -R ⁴ :

[0092]

Embedded image And other substituents are as described above.

Certain compounds of the present invention include, but are not limited to, the following:

[0094]

Embedded image The compounds of the present invention may contain one or more "asymmetric" carbon atoms and may thus give rise to racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Each stereogenic carbon can be of the R or S configuration. Certain compounds and scaffolds exemplified herein are:
Compounds and scaffolds that can be shown in a particular stereochemical configuration, but have either the opposite stereochemical structure at any given chiral center or mixtures thereof are also envisioned.

[0095] All such isomeric forms of these compounds, as well as their pharmaceutically acceptable derivatives, are expressly included in the present invention.

The term “pharmaceutically acceptable derivative” means a pharmaceutically acceptable salt, ester, or salt of such an ester of a compound of the present invention or any other compound, Upon administration to a recipient, it may provide (directly or indirectly) a metabolite or residue of a compound of the present invention or anti-ICE activity.

Pharmaceutically acceptable salts of the compounds of the present invention include, for example, salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric Acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, but are useful as intermediates in obtaining the compounds of the present invention and their addition salts of pharmaceutically acceptable acids Can be used for the preparation of Salts derived from appropriate bases include alkali metals (
For example, sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C ₁ ~ ₄ alkyl) ₄ ⁺ salts.

The present invention also contemplates “quaternization” of any of the basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any of the reagents known to those skilled in the art, including, for example, lower alkyl halides such as methyl chloride, methyl bromide and methyl iodide, ethyl chloride, Ethyl and ethyl iodide, propyl chloride, propyl bromide and propyl iodide and butyl chloride, butyl bromide and butyl iodide); dialkyl sulfates (including dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate); long chains Halides (eg, decyl chloride, decyl bromide and decyl iodide, lauryl chloride, lauryl bromide and lauryl iodide, myristyl chloride, myristyl bromide and myristyl iodide and stearyl chloride, stearyl bromide and stearyl iodide); and Aralkyl halides (benzyl bromide and phenethyl bromide Including a), and the like. Water or oil-soluble or dispersible products can be obtained by such quaternization.

When substituted plurally, each substituent may be independently selected from any other substituent as long as a stable compound is formed by a combination of the substituents.

The combinations of substituents and variables envisioned by the present invention are merely those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that is sufficiently stable to allow it to be manufactured and administered to a mammal by methods known in the art. Typically, such compounds are
It is stable for at least one week at temperatures below 0 ° C. in the presence or absence of moisture or other chemically reactive conditions.

Preferred compounds of the present invention, upon oral administration, can be readily absorbed by the bloodstream of the patient. This oral availability makes such compounds an excellent agent for oral treatment and prophylaxis for IL-1 mediated, apoptosis mediated, IGIF mediated or IFN-γ mediated diseases.

It is to be understood that the compounds of the present invention may exist in different equilibrium forms, depending on the choice of solvent, pH, and conditions including others known to those skilled in the art. All such forms of these compounds are expressly included in the present invention. In particular, many compounds of the present invention, especially those containing an aldehyde or ketone group and a carboxylic acid group in Y, can be in hemiacetal or hemiketal or hydrated form. For example, when Y is the compound of embodiment (A) is in hemiacetal or hemiketal form:

[0103]

Embedded image Depending on the choice of solvent and other conditions known to the person skilled in the art, the compounds according to the invention can also take the hydrated, acyloxyketal, acyloxyacetal, ketal, acetal or enol form. For example, a compound of the present invention is in a hydrated form when Y is:

[0104]

Embedded image And R ⁸ is H; when Y is: in acyloxy ketal or acyloxy acetal form:

[0105]

Embedded image When Y is: in ketal or acetal form:

[0106]

Embedded image When Y is the following is the enol form:

[0107]

Embedded image Furthermore, it is to be understood that the equilibrium forms of the compounds of the invention may include tautomeric forms. All such forms of these compounds are expressly included in the present invention.

The compounds of formulas (I) and (II) can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

The compounds of the present invention are one of the most easily synthesized known caspase inhibitors.
One. Many of the previously described caspase or ICE inhibitors have 4
It contains the above chiral center and numerous peptide bonds. The relatively easy synthesis of the compounds of the present invention shows advantages in large-scale production of these compounds.

For example, the compounds of the invention can be prepared using the processes described herein. As will be appreciated by those skilled in the art, these processes are not the only means by which the compounds described and claimed in this application can be synthesized. Further, methods will be apparent to those skilled in the art. Furthermore, the various synthetic steps described herein may be performed in an alternating sequence or order to obtain the desired compounds.

It is to be understood that the compounds of the present invention can be modified by appropriate functionalities to enhance selective biological properties. Such modifications are known in the art, and modifications that increase biological permeability and increase oral availability in a given biological system (eg, blood, lymphatic system, central nervous system). And modifications that increase solubility to allow administration by injection, alter metabolism, and alter elimination rates. Further, the compounds of the present invention can be converted to a prodrug form, such that the desired compound is produced in the patient as a result of the action of metabolism or other biochemical processes on the prodrug. . Such prodrug forms typically demonstrate little or no activity in in vitro assays. Some examples of prodrug forms include the ketal, acetal, oxime, imine and hydrazone forms of compounds containing a ketone or aldehyde group, particularly where these occur at the Y group of the compounds of the present invention. Other examples of prodrug forms include the hemiketal, hemiacetal, acyloxyketal, acyloxyacetal, ketal, acetal, and enol forms described herein.

Compositions and Methods The compounds of the present invention are caspase inhibitors, especially ICE inhibitors. Thus, these compounds may target and inhibit events in IL-1 mediated, apoptosis mediated, IGIF mediated and IFN-γ mediated diseases, thereby
Inflammatory disease, autoimmune disease, destructive bone
, The ultimate activity of the protein in proliferative disorders, infectious diseases, and degenerative diseases. For example, compounds of the present invention inhibit the conversion of precursor IL-1β to mature IL-1β by inhibiting ICE. Because ICE is essential for the production of mature IL-1, inhibition of that enzyme inhibits the production of mature IL-1 and thereby inhibits IL-1 mediated physiological effects and conditions (eg, inflammation). Effectively blocks the start of Therefore, by inhibiting the activity of IL-1β precursor, the compounds of the present invention effectively function as IL-1 inhibitors.

The compounds of the present invention also inhibit the conversion of pro-IGIF to active and mature IGIF by inhibiting ICE. Since ICE is essential for the production of mature IGIF, inhibition of ICE can be achieved by inhibiting production of mature IGIF.
It effectively blocks the onset of IF-mediated physiological effects and symptoms. IGIF is then essential for IFN-γ production. Therefore, ICE is
Inhibiting the production of F, and therefore of IFN-γ, effectively blocks the onset of IFN-γ-mediated physiological effects and symptoms.

Accordingly, the pharmaceutical compositions and methods of the present invention are useful for controlling caspase activity in vivo. Thus, the compositions and methods of the present invention can
Useful for controlling L-1 levels, IGIF levels or IFN-γ levels, and progressing IL-1 mediated, apoptosis mediated, IGIF mediated or IFN-γ mediated conditions (including disease, disorder or effect) Useful for treating or reducing the severity or effect.

The pharmaceutical compositions of the present invention comprise a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Such compositions may optionally include additional therapeutic agents. Such agents include anti-inflammatory agents, matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antiviral agents, cytokines, growth factors, immunomodulators, prostaglandins or anti-vascular hyperproliferative compounds But are not limited to these.

The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier that can be administered to a patient together with a compound of the present invention, without impairing the pharmacological activity of the compound.

[0117] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include:
Ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate), glycine, sorbic acid, potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids, Water, salt or electrolyte (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium Carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, wool fat and self-emulsifying drug delivery system (SEDDS) (eg, α-tocopherol, polyethylene glycol 1000 succinate), Although it includes other similar polymeric delivery matrices, but are not limited to.

In pharmaceutical compositions containing only compounds of formula (I) or (II) as the active ingredient, the method for administering these compositions further comprises the step of administering an additional agent to the subject. obtain. Such agents include anti-inflammatory agents, matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antiviral agents, cytokines, growth (growth) factors, immunomodulators, prostaglandins or antivascular agents Including but not limited to hyperproliferative compounds.

The term “pharmaceutically effective amount” refers to an amount effective in treating or ameliorating an IL-1 mediated disease, apoptosis mediated disease, IGIF mediated disease or IFN-γ mediated disease in a patient. The term “prophylactically effective amount” refers to an amount effective to prevent or substantially reduce an IL-1 mediated disease, an apoptosis mediated disease, an IGIF mediated disease or an IFN-γ mediated disease in a patient.

The compounds of the present invention control IGIF or IFN-γ levels in vivo and treat diseases mediated by IL-1, apoptosis, IGIF or IFN-γ, or have their effects progressed or It can be used in the usual manner to reduce the severity. Methods of such treatment, their dosage levels and requirements can be selected by those skilled in the art from available methods and techniques.

For example, compounds of the present invention may be useful in treating IL-1 mediated diseases, apoptosis mediated diseases, IG
To administer to a patient suffering from an IF-mediated disease or an IFN-γ-mediated disease in a pharmaceutically acceptable manner and in an amount effective to reduce the severity of the disease, a pharmaceutically acceptable It can be combined with an adjuvant.

Alternatively, the compounds of the present invention may be administered as IL-1 mediated diseases, apoptosis mediated diseases, I
It can be used in compositions and methods for treating or protecting individuals against GIF or IFN-γ mediated diseases for extended periods of time. These compounds are
It can be used in such compositions, either alone or with other compounds of the invention, in a manner consistent with the normal usage of enzyme inhibitors in pharmaceutical compositions. For example, the compounds of the present invention can be combined with pharmaceutically acceptable adjuvants commonly used in vaccines and against IL-1 mediated diseases, apoptosis mediated diseases, IGIF mediated diseases or IFN-γ mediated diseases. Can be administered in a prophylactically effective amount to protect the individual over time.

The compounds of formula (I) or (II) may also be used to enhance the efficacy of treatment or prevention against various IL-1 mediated diseases, apoptosis mediated diseases, IGIF mediated diseases or IFN-γ mediated diseases. It can be co-administered with caspases or other ICE inhibitors.

In addition, the compounds of the present invention may be used in combination with either conventional anti-inflammatory agents or with matrix metalloprotease inhibitors, lipoxygenase inhibitors, and antagonists of cytokines other than IL-1β.

The compounds of the present invention may also be used to prevent or combat IL-1 mediated disease symptoms (eg, inflammation), such as immunomodulators (eg, bropyrimine, anti-human alpha interferon antibody, IL-2, GM). -CSF, methionine enkephalin, interferon-α, diethyldithiocarbamate, tumor necrosis factor, naltrexone and EPO), prostaglandins, or antiviral agents (eg, 3TC, polysulfate polysaccharides, ganciclovir, ribavirin, acyclovir, α-interferon, trimethotrexate and fanciclovir) or a prodrug or related compound thereof may be administered.

When administering the compounds of the present invention in combination therapy with other agents, they may be administered to the patient sequentially or simultaneously. Alternatively, a pharmaceutical or prophylactic composition according to the invention may comprise a combination of a compound of formula (I) or (II) and another therapeutic or prophylactic agent.

The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically.
It can be administered rectally, nasally, buccally, vaginally, or via an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein refers to subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection techniques or infusions. Including technology.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Can be Acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
Fatty acids (eg, oleic acid) and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils (eg, olive oil or castor oil, especially their polyoxyethylated types). Useful. These oil solutions or suspensions can also be used as long-chain alcohol diluents or dispersants (eg, Ph
(Diluents or dispersants as described in armopeia Helvetica), or similar alcohols.

The pharmaceutical compositions of the present invention can be administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. It can be administered orally. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. lubricant(
For example, magnesium stearate) is also typically added. Useful diluents for oral administration in a capsule form include lactose and dried corn starch. When administering an aqueous suspension orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.
These compositions comprise a compound of the present invention and a suitable nonirritating excipient, which is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the active ingredient ) Can be prepared by mixing Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

Topical administration of the pharmaceutical compositions of this invention is particularly useful when the desired treatment involves areas or organs that can be easily accessed by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active component suspended or dissolved in a carrier. Carriers for topical administration of a compound of the present invention include mineral oil, liquefied petroleum, white petroleum.
m), propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsified wax and water, but are not limited thereto. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl (c
etearyl) alcohols, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be applied locally to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present invention.

A pharmaceutical composition of the invention may be administered by nasal aerosol or inhalation.
Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations, and as solutions in saline, benzyl alcohol or other suitable preservatives, to increase bioavailability. An absorption promoter, a fluorocarbon, and / or
Alternatively, they can be prepared using other solubilizing or dispersing agents known in the art.

About 0.01 to about 100 mg / kg body weight of the active ingredient compound per day, preferably 0.5 to about 75 mg / kg body weight per day, most preferably about 1 mg / kg per day Dosage levels from body weight to 50 mg / kg body weight include I
Useful for monotherapy for the prevention and treatment of L-1 mediated diseases, apoptosis mediated diseases, IGIF mediated diseases or IFN-γ mediated diseases: inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders , Infectious diseases, degenerative diseases, necrotic diseases, inflammatory peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma , Chronic thyroiditis,
Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease , Crohn's disease, psoriasis, graft-versus-host disease, osteoporosis, multiple myeloma-related bone disorders, acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock , Bacterial dysentery, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AI
DS-related encephalitis, HIV-related encephalitis, aging, alopecia, seizure neurological damage, ulcerative colitis, traumatic brain injury, organ transplant rejection, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis Eczema, primary cirrhosis, uveitis, Behcet's disease, atopic dermatosis, erythroblastosis, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, and excessive drinking of alcohol or viruses (eg. , HBV, HCV
HGV, yellow fever virus, dengue virus and Japanese encephalitis virus), which have localized effects on the liver or other organs with inflammatory or apoptotic components.

Typically, the pharmaceutical compositions of this invention will be administered from about 1 to 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute treatment. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Preferably, such preparations contain from about 20% to about 80% active compound.

Where the composition of the invention contains a combination of a compound of Formula (I) or (II) and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent may be in a monotherapy regime. Should be present at a dosage level of between about 10% to 80% of the dosage normally administered.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the symptoms are alleviated to the desired level and, if treatment is to be stopped, the improved condition is retained. However, patients may require intermittent treatment for the long-term basis of any recurrence or disease symptoms.

As one of skill in the art will appreciate, lower or higher doses than those described above may be required. The particular dosage and treatment regime for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, weight, general health, gender, diet, time of administration, excretion rate, Drug combinations, the severity and course of the disease, and the patient's predisposition to the disease, and the judgment of the treating physician).

[0138] IL-1 mediated or apoptosis mediated diseases can be treated or prevented by the compounds of the present invention. Such diseases include inflammatory diseases, autoimmune diseases,
These include, but are not limited to, destructive bone disorders, proliferative disorders, infectious diseases and degenerative diseases.

[0139] IL-1 mediated or apoptosis mediated diseases that can be treated or prevented include, but are not limited to, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, inflammatory peritonitis and adult respiratory distress Not done. Preferably, the inflammatory disease is osteoarthritis or acute pancreatitis.

IL-1 mediated autoimmune diseases or apoptosis mediated diseases that can be treated or prevented include glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis , Insulin-dependent diabetes (
Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, and host versus host Sex transplant diseases include, but are not limited to. Preferably, the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, or psoriasis.

[0141] IL-1 or apoptosis-mediated destructive bone disorders that can be treated or prevented include osteoporosis and multiple myeloma-related bone disorders,
It is not limited to these.

[0142] IL-1 mediated or apoptotic mediated proliferative disorders that can be treated or prevented include acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma. However, it is not limited to these.

[0143] IL-1 mediated or apoptosis mediated infectious diseases that can be treated or prevented include, but are not limited to, sepsis, septic shock, and shigellosis.

[0144] IL-1 mediated or apoptotic mediated degenerative or necrotic diseases that can be treated or prevented by the compounds of the present invention include Alzheimer's disease, Parkinson's disease, cerebral ischemia, and myocardial ischemia. Not limited. Preferably, the degenerative disease is Alzheimer's disease.

IL-1 mediated or apoptosis mediated degenerative diseases that can be treated or prevented by the compounds of the present invention include Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis , AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, and neurological damage from stroke.

[0146] Other diseases having an inflammatory or apoptotic component may be treated or prevented by the compounds of the present invention. Such a disease can be a disease having a localized effect on the liver or other organs or a systemic disease, such as excessive dietary alcohol consumption or a virus (eg, HBV, HCV, HGV, yellow fever virus) , Dengue virus and Japanese encephalitis virus).

[0147] IGIF- or IFN-γ-mediated diseases can also be treated or prevented by the compounds of the present invention. Such diseases include, but are not limited to, inflammatory conditions, infectious conditions, autoimmune conditions, proliferative conditions, neurodegenerative diseases and necrotic conditions. IGIF-mediated inflammatory diseases or IFN-γ-mediated inflammatory diseases that can be treated or prevented include osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis , Cerebral ischemia, myocardial ischemia and adult respiratory distress. Preferably, the inflammatory disease is rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, hepatitis or adult respiratory distress.

[0148] IGIF- or infectious diseases that can be treated or prevented include, but are not limited to, infectious hepatitis, sepsis, septic shock, and shigellosis.

[0149] IGIF-mediated or IFN-γ-mediated autoimmune diseases that can be treated or prevented include glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, Insulin-dependent diabetes mellitus (type I), juvenile diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia,
Myasthenia gravis, multiple sclerosis, psoriasis, lichen planus, graft-versus-host disease, acute dermatomyositis, eczema, primary cirrhosis, hepatitis, uveitis, Behcet's disease, atopic dermatosis, erythroblastosis , Aplastic anemia, amyotrophic lateral sclerosis and nephrotic syndrome, but are not limited thereto. Preferably, the autoimmune disease is glomerulonephritis, insulin-dependent diabetes mellitus (type I), juvenile diabetes, psoriasis, graft-versus-host disease or hepatitis.

More preferred diseases that can be treated or prevented by the compounds of the present invention include rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), inflammatory peritonitis, septic shock, flu, These include traumatic brain injury, organ transplant rejection, osteoarthritis, and asthma.

Accordingly, one embodiment of the present invention provides a method for treating or preventing an IL-1 mediated or apoptosis mediated degenerative disease in a subject, the method comprising: Any of the compounds described herein, pharmaceutical compositions,
Or administering a combination and a pharmaceutically acceptable carrier.

Another embodiment of the present invention provides a method for reducing the production of IGIF in a subject, the method comprising: administering to the subject any of the compounds, pharmaceutical compositions, or pharmaceutical compositions described herein. Or combining and administering a pharmaceutically acceptable carrier.

Another embodiment of the present invention provides a method of reducing the production of IFN-γ in a subject, the method comprising: administering to the subject any of the compounds, pharmaceutical compositions described herein, Administering a substance, or combination, and a pharmaceutically acceptable carrier.

The present invention relates to IL-1 mediated diseases, apoptosis mediated diseases, IGIF mediated diseases, I
Although focused on the use of the compounds disclosed herein to prevent and treat FN-γ mediated diseases, the compounds of the present invention can also be used as inhibitors of other cysteine proteases.

The compounds of the present invention may also include caspases or other cysteine proteases (IC
(Including, but not limited to E). As commercial reagents, the compounds of the invention and their derivatives can be used to block proteolysis of target peptides in biochemical or cellular assays for ICE and ICE homologs, or can be derivatized to affinity Combined (tethe) for chromatographic applications
red) As a substrate, it can be bound to a stable resin. These and other uses that characterize commercially available cystine protease inhibitors will be apparent to those skilled in the art.

To better understand the present invention, the following examples are set forth. These examples are for illustrative purposes only and should not be construed in any way as limiting the scope of the invention.

General Methods The compounds of the present invention can be evaluated in various biological assays, including the assays described in Examples 2-4.

Other assays that can be used to evaluate compounds of the invention are described in
PCT / US96 / 20843 published on March 26 (publication number WO97 / 22619)
) (Which is incorporated herein by reference). Such assays include in vivo bioavailability determination, pharmacokinetic studies in mice, IC
Inhibition of E-homologs, inhibition of apoptosis, in vivo acute assays for anti-inflammatory efficacy, measurement of blood levels, IGIF assays, carrageenan peritoneal inflammation assays, and type II collagen-induced arthritis.

Example 1 Compounds of the present invention were prepared using published procedures (eg, Robl, JA, et al., Bioorg. Med. Chem. Lett. 4, incorporated by reference herein).
, Pp. 20555-2060 (1994) or U.S. Patent No. 4,465,679). One skilled in the art understands that such procedures can be modified to obtain compounds of the present invention.

For example, compounds represented by formula (Ia) or (Ib) can be prepared as described in Scheme 1.

[0161]

Embedded image For example, compounds represented by Formula (Ic) or (Id) can be prepared as described in Scheme 2.

[0162]

Embedded image For example, a compound represented by the formula (IIa) or (IIb)
Can be prepared as described in

[0163]

Embedded image For example, a compound represented by the formula (IIc) or (IId) is converted to a compound represented by Scheme 4
Can be prepared as described in

[0164]

Embedded image Compounds represented by formula (I) or (II) wherein R ¹⁹ and Y together with the nitrogen atom to which they are attached form a ring (g) are described as described in Scheme 5. Can be prepared.

[0165]

Embedded image Scheme 5 describes the synthesis of compounds where m is 0. Compounds where m is 1 can be prepared by analogous methods. N-alloc protected amines can be protected with other groups well known to those skilled in the art. The palladium coupling method is described in PCT application PCT / US96 / 20843 (publication number WO97), which is incorporated herein by reference.
/ 22619).

Schemes 1-5 describe the synthesis of certain embodiments of the invention. Other embodiments can be prepared by similar methods.

Example 2 1. Enzyme Assay Using UV-Visible Substrate This assay is performed using a succinyl-Tyr-Val-Ala-Asp-p-nitroanilide substrate. The synthesis of similar substrates is described in L. et al. A. Reiter (Int
. J. Peptide Protein Res. , 43, pp. 87-96 (19
94)). This assay mixture contains the following: 65 μl buffer (10 mM Tris, 1 mM DTT, 0.1% CHAP)
S ＠ pH 8.1) 10 μl ICE (50 nM final concentration to obtain a rate of about 1 mOD / min) 5 μl DMSO / inhibitor mixture 20 μl 400 μM substrate (80 μM final concentration) 100 μl Total reaction volume.

This visible ICE assay is performed in a 96-well microtiter plate. To this well, add buffer, ICE and DMSO (if inhibitors are present) in the order listed here. These components are left to incubate at room temperature for 15 minutes, starting from when all components are present in all wells.
The microtiter plate reader is set to incubate at 37 ° C. After a 15 minute incubation, the substrate was added directly to the wells and the reaction was allowed to proceed at 405-603 nm chromophore (pNA) at 37 ° C. for 20 minutes.
) Is monitored by tracking the release. Linear fitting of data (l
Perform an inear fit and calculate the rate in mOD / min. In experiments containing inhibitors, only DMSO was present; in other experiments, a volume of 100
Use buffer to make μl.

2. Enzyme Assay Using Fluorescent Substrates The assay was essentially performed by Thornbury et al., Nature, 356, 76.
According to pages 8-774 (1992), using substrate 17 referenced in that article. The substrate is acetyl-Tyr-Val-Ala-Asp-amino-4-methylcoumarin (AMC). Mix the following components: 65 μl buffer (10 mM Tris, 1 mM DTT, 0.1% CHAP
S ＠ pH 8.1) 10 μl ICE (2-10 nM final concentration) 5 μl DMSO / inhibitor solution 20 μl 150 μM substrate (30 μM final) 100 μl Total reaction volume.

The assay is performed in a 96-well microtiter plate. Buffer and ICE
To the wells. The components are left to incubate at 37 ° C. for 15 minutes in a temperature-controlled well plate. After a 15 minute incubation, the reaction is started by adding the substrate directly to the wells and the reaction is allowed to proceed at 37 ° C. for 30 minutes, 3 minutes.
It is monitored by following the emission of the AMC fluorophore using an excitation wavelength of 80 nm and an emission wavelength of 460 nm. A linear fit of the data is performed for each well, and the rate is determined in units of fluorescence per second.

For determination of the enzyme inhibition constant (K _i ) or determination of the mode of inhibition (competitive, uncompetitive, or non-competitive), the kinetic data determined at various inhibitor concentrations in the enzyme assay are standardized. Computer fitting to enzyme kinetic equations (IH Segel, Enzyme Kinetics, Wiley)
-Interscience, 1975).

The determination of the second order rate constant of an irreversible inhibitor is determined by Morrison's progress equation
(The progress equation), phosphor vs. time
The data was fitted and performed. See Morrison, J.M. F. , Mol
. Cell. Biophys. , 2, 347-368 (1985). Thor
nberry et al. describe the measurement of the rate constant of an irreversible inhibitor of ICE.
, Published a description of these methods. Thornberry, N.M. A. Et al., Bio
chemistry, 33, 3923-3940 (1994). Preceding compound
For compounds for which body formation cannot be observed kinetically, the second-order rate constant (K_inact ) Is k_obs It is derived directly from the slope of a linear plot of inhibitor concentration [I]. For compounds where a prior complex formation to the enzyme can be detected, K _obs The hyperbolic plot of [I] versus K_iAnd k '. Then, the second-order rate constant k_inactTo K '/ K_iGive by

3. PBMC Cell Assay Human peripheral blood mononuclear cells (PBMC) or enriched adhesion (Enriched Adh)
erent) IL-1β assay using a mixed population of mononuclear cells Processing of pre-IL-1β by ICE can be measured using various cell sources in cell culture. Human PBMCs obtained from healthy donors provide a mixed population of lymphocyte subtypes and mononuclear cells, which produce a spectrum of interleukins and cytokines in response to many classes of physiological stimulants.
Adherent mononuclear cells from PBMC provide an enriched source of normal monocytes for the selective study of cytokine production by activated cells.

Experimental Procedures Prepare a series of initial dilutions of test compounds in DMSO or ethanol, followed by RPMI-10% FBS medium (2 mM L-glutamine, 10 mM HEPE
S, containing 50 U and 50 ug / ml pen / strep, respectively) to obtain the drug at four times (4 ×) the final test concentration containing 0.4% DMSO or 0.4% ethanol. . The final concentration of DMSO is 0.1% for all drug dilutions. A concentration titration that takes the apparent K _i for the test compound as determined in the ICE inhibition assay into account is generally used for initial compound screening.

Generally, 5-6 compound dilutions are tested, and assays of the cellular components are performed in duplicate, using duplicate ELISA determinations on each cell culture supernatant.

PBMC Isolation and IL-1 Assay Buffy coat cells isolated from a pint of human blood (resulting in a final volume of 40-45 ml of plasma and cells) were diluted to 80 ml with media and 10 ml of the cell suspension was each overlaid on a LeukoPREP separation tube (Becton Dickinson). After centrifugation at 1500-1800 × g for 15 minutes, the plasma / media layer is aspirated, and the mononuclear cell layer is collected with a Pasteur pipette and transferred to a 15 ml conical centrifuge tube (Corning). Medium is added to a volume of 15 ml, the cells are mixed gently by inversion and centrifuged at 300 xg for 15 minutes. The PBMC pellet is resuspended in a small volume of medium, the cells are counted and adjusted to 6 × 10 ⁶ cells / ml.

For cell assays, 24-well flat bottom tissue culture plates (Corning)
Of each well (0.5 ml of test compound dilution and 0.5 ml of LPS solution (Sig
ma # L-3012; 20 ng / ml solution prepared in complete RPMI medium; 5 ng / ml final LPS concentration), add 1.0 ml of cell suspension. Addition of 0.5 ml each of test compound and LPS is usually sufficient to mix the contents of the wells. Three control mixtures are run per experiment, either with LPS alone, solvent vehicle controls, and / or additional media to adjust the final culture volume to 2.0 ml. The cell culture is incubated at 37 ° C. for 16-18 hours in the presence of 5% CO ₂ .

At the end of the incubation period, cells are harvested and transferred to a 15 ml conical centrifuge tube. After centrifugation at 200 × g for 10 minutes, the supernatant is collected and transferred to a 1.5 ml Eppendorf tube. The cell pellet is pre-IL-1β
It can be noted that Western blotting or ELISA with specific antisera can be used for biochemical assessment of pre-IL-1β and / or mature IL-1β content in cytosolic extracts.

Isolation of adherent mononuclear cells PBMCs are isolated and prepared as described above. Medium (1.0 ml) is added to the wells first, followed by 0.5 ml of the PBMC suspension. After a 1 hour incubation, the plate is gently shaken and non-adherent cells are aspirated from each well. The wells are then washed gently three times with 1.0 ml of medium and finally resuspended in 1.0 ml of medium. Enrichment of adherent cells generally yields 2.5-3.0 × 10 ⁵ cells per well. Addition of test compound, LPS, cell incubation conditions, and processing of the supernatant proceed as described above.

ELISA The Quantikine kit (R & D Systems) can be used for the measurement of mature IL-1β. The assay is performed according to the manufacturer's instructions. PBMC
About 1 to 3 ng / m 2 in both the and the adherent mononuclear cell positive control.
1 mature IL-1β level is confirmed. ELISA assays are performed with 1: 5, 1:10, and 1:20 supernatant dilutions to select the optimal dilution of the supernatant in the test panel, derived from the LPS-positive control.

The inhibitory potency of a compound can be represented by an IC ₅₀ value, which is the inhibitor concentration at which 50% of mature IL-1β is detected in the supernatant compared to the positive control.

[0182] One skilled in the art will understand that the values obtained in cellular assays may depend on a variety of factors. That value may not always represent a definitive quantitative result.

Example 3 Whole Blood Assay for IL-1β Production Whole blood assay IC ₅₀ values for compounds of the present invention were obtained using the method described below.

Objectives The whole blood assay is a simple method for measuring IL-1β (or other cytokine) production and the activity of potential inhibitors. The complexity of this assay system with its complete complement of lymphoid and inflammatory cell types, the spectrum of plasma proteins and the erythrocytes are ideal in vitro examples of human physiological conditions in vivo.

(Materials) Pyrogen-Free Syringe (about 30 cc) Sterile pyrogen-free vacuum tube containing lyophilized Na ₂ EDTA (4.5 mg / 10 ml tube) Human whole blood sample (about 30- 50 cc) 1.5 ml Eppendorf tube Test compound stock solution (about 25 mM in DMSO or other solvent) Endotoxin-free sodium chloride solution (0.9%) and HBSS lipopolysaccharide (Sigma; Cat. # L-3012) ) In HBSS at 1 mg /
ml of stock solution IL-1β ELISA kit (R & D Systems; Cat #
DLB50) TNFα ELISA kit (R & D Systems; Cat # D
TA50) Water bath or incubator.

(Whole Blood Assay Experimental Procedure) Set the incubator or water bath at 30 ° C. 0.25 blood
Divide into ml aliquots and place in 1.5 ml eppendorf tubes. Note: Ensure that the whole blood sample tube is inverted after every two aliquots. Differences in replicates can result if the cells precipitate and are not evenly suspended. The use of a positive displacement pipette also minimizes differences between replicate aliquots.

Dilutions of drug in sterile pyrogen-free saline are prepared by serial dilution
I do. Apparent K for the test compound as determined in the ICE inhibition assay _i A series of dilutions that do not take into account considerations are generally used for initial compound screening. For extremely hydrophobic compounds, new
Compounds in fresh plasma or in 5% DMSO with PBS to enhance solubility
Prepare a product dilution.

Add 25 μl of test compound dilution or vehicle control and mix the samples gently. Then add 5.0 μl of LPS solution (stored at 250 ng / ml and freshly prepared: LPS final concentration 5.0 ng / ml) and mix again. Incubate the tubes at 30 ° C. for 16-18 hours in a water bath with occasional mixing. Instead, place the tubes in the same incubation time,
It can be placed in a rotator set at 4 rpm. This assay is
Should be set in duplicate or triplicate, with the following controls: negative control-no LPS; positive control-no test inhibitor; vehicle control-the highest concentration of DMSO or compound solvent used in the experiment. Additional saline is added to all control tubes to normalize the volume for both control and experimental whole blood test samples.

After the end of the incubation period, the whole blood sample was transferred to a microcentrifuge (micro).
centrifuge at approximately 2000 rpm for 10 minutes, transfer the plasma to a fresh microcentrifuge tube, and if necessary, pellet to remove residual platelets.
Centrifuge at 000 × g. Plasma samples may be stored frozen at -70 C before assaying for cytokine levels by ELISA.

(ELISA) R & D Systems (614 McKinley Place N.
E. FIG. The Quantikine kit of Minneapolis, MN 55413) can be used for the measurement of IL-1β and TNFα. The assay is performed according to the manufacturer's instructions. Within a range of individuals, IL-1β levels of about 1-5 ng / ml in positive controls can be observed. A 1: 200 dilution of plasma for all samples was performed using ELISA
Usually sufficient to fall within the linear range of the SA standard curve. If differences are found in the whole blood assay, it may be necessary to optimize the standard dilution. Nerad, J
. L. J. et al. Leukocyte Biol. , 52, 687-692 (1
992).

Example 4 The antiviral efficacy of a compound can be evaluated in various in vitro and in vivo assays. For example, compounds can be tested in an in vitro virus replication assay. In vitro assays may use whole cells or isolated cellular components. In vivo assays include animal models for viral diseases. Examples of such animal models include, but are not limited to, a rodent model for HBV or HCV infection, a woodchuck model for HBV infection, and a chimpanzee model for HVC infection.

Compounds of the invention may also be evaluated in animal models for dietary alcohol-induced disease.

Example 5 Compounds 10a-10d, and 11a-11d were prepared as described below:

[0194]

Embedded image (Preparation of (N-benzyloxycarbonyl-hydrazino) -acetic acid tert-butyl ester (1)). Benzyl carbamate (25.0 g, 150 mmol) in 230 mL of dimethylformamide (DMF), potassium carbonate (20.
78 g, 150 mmol) in a mixture of tert-butyl bromoacetate (2
6.4 g, 145 mmol) were added. This suspension was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1000 mL of ethyl acetate, washed with ice water,
It was then washed three times with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under vacuum to give a clear oil. This is treated with hexane / EtO
Purification by flash chromatography using Ac (9/1 to 7/3) afforded 23.55 g (62% yield) of the title compound. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.45 (s, 9H), 3.55 (s, 2H), 4.20 (br, 1H), 5.15 (s, 2H), 6. 70 (br, 1H), 7.40
(S, 5H). Analytical HPLC ★: 10.11 minutes.

(Preparation of 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -glutaric acid 5-benzyl ester (2)). Toluene (150 mL
A mixture of γ-benzyl-1-glutamate (11.85 g, 50 mmol) and phthalic anhydride (7.40 g, 50 mmol) in Dean-Stark
The mixture was refluxed for 16 hours using a tube. The solvent was removed under reduced pressure. The residue is purified by flash chromatography using hexane / ethyl acetate / acetic acid (90/10/1 to 50/50/1) to give 14.83 g (80% yield).
The title compound was obtained. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 2.40-2
. 70 (m, 4H), 4.95 to 5.10 (m, 3H), 7.27 to 7.40 (
m, 5H), 7.70-7.95 (m, 4H). Analytical HPLC: 13.28 minutes. LC-MS (ES ^<+> ): m / e = 368 (M + H ^< + ^> ).

(5- (N′-benzyloxycarbonyl-N-tert-butoxycarbonylmethyl-hydrazino) -4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -5 Preparation of oxo-pentanoic acid benzyl ester (3)). 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -glutaric acid 5-benzyl ester (2) in 25 mL of dichloromethane with 0.1 mL of dimethylformamide (DMF) (2) ( 1.84 g, 5 mm
ol) at 0 ° C. in oxalyl chloride (666 mg, 5.25 mmol).
Was added dropwise. The solution was stirred at 0 ° C. for 30 minutes and then at room temperature for 1 hour. K ₂ CO ₃ (1.03 g) was added at 0 ° C., followed by (N-benzyloxycarbonyl-hydrazino) -acetic acid tert-butyl ester (1) (1.40 g, 5 mmol) in 5 mL of dichloromethane. The solution was added. The mixture was stirred at room temperature for 16 hours. The solvent is removed under reduced pressure and the residue is
Suspended in 0 mL of ethyl acetate, washed with water (200 mL × 2), and then with brine (200 mL × 2). The organic layer is dried over anhydrous Na ₂ SO ₄
Filter and concentrate under vacuum to give 2.8 g of a clear oil. By flash chromatography using hexane / ethyl acetate (9/1 to 7/3), 1
. 93 g (61% yield) of the title compound were obtained. ^{1 H-NMR (500MHz, C} DCl 3) δ1.35 (s, 9H), 2.30~2.55 (m, 4H), 4.7 0~5.20 (br, 4H), 5.08 (S, 2H), 5.30 (m, 1H),
7.26 to 7.35 (m, 10H), 7.65 to 7.90 (m, 4H). Analytical HPLC: 14.6 minutes. LC-MS (ES ^<+> ): m / e = 630 (M + H ^< + ^> ).

([6- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -3,7-dioxo- [1,2] diazepan-1-yl] -acetic acid Preparation of tert-butyl ester (4)). Tetrahydrofuran (TH
F) (30 mL) and DMF (3 mL) in 5- (N′-benzyloxycarbonyl-N-tert-butoxycarbonylmethyl-hydrazino) -4- (1
, 3-Dioxo-1,3-dihydro-isoindol-2-yl) -5-oxo-pentanoic acid benzyl ester (3) and 10% palladium on carbon (25
0 mg) was stirred under a hydrogen atmosphere for 16 h. This mixture is Cel
Filtered through ite and the filtrate was evaporated under vacuum. This residue was dissolved in 30 mL of dichloromethane. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (770 mg, 4 mmol) was added and the solution was stirred at room temperature for 3.5 hours. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (300 mL), then water (100 m
L × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and purified by flash chromatography using hexane / ethyl acetate (85/15 to 50/50) to give 1.06 g (75% yield) ) Was obtained.

[0198]

(Equation 1) ([2-benzyl-6- (1,3-dioxo-1,3-dihydro-isoindole-2-yl) -3,7-dioxo- [1,2] diazepan-1-yl] -acetic acid tert -Preparation of butyl ester (5a)). [6- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -3,7- in THF (5 mL).
Dioxo- [1,2] diazepan-1-yl] -acetic acid tert-butyl ester (4) (200 mg, 0.52 mmol), benzyl bromide (110 mg, 0.6
4 mmol), a mixture of K ₂ CO ₃ (125 mg, 0.9 mmol) and benzyltriethylammonium chloride (15 mg) was stirred at room temperature for 40 hours. The mixture was diluted with ethyl acetate (100 mL) and washed three times with water. The organic layer was dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was purified by flash chromatography using dichloromethane / ethyl acetate (99.5 / 0.5-97.5 / 2.5) to give 166 mg (67% yield) of the title compound.

[0199]

(Equation 2) [2-allyl-6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3,7-dioxo- [1,2] diazepan-1-yl] -acetic acid tert- The butyl ester (5b) was synthesized from 4 and allyl bromide by the method and chromatography used to prepare 5a to give 388 mg (
The yield was 91%).

[0200]

(Equation 3) ([6- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -3,7-dioxo-2-propyl- [1,2] diazepan-1-yl] -acetic acid tert- Preparation of butyl ester (5c)). In ethanol (10 mL)
[2-allyl-6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3,7-dioxo- [1,2] diazepan-1-yl] -acetic acid tert- A mixture of butyl ester (5b) (380 mg, 0.89 mmol) and 20% palladium (II) hydroxide on carbon (Pearlman's catalyst) (80 mg) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and the filtrate was evaporated under vacuum to give 380 mg (99.5% yield) of the title compound.

[0201]

(Equation 4) ((6-amino-2-benzyl-3,7-dioxo- [1,2] diazepan-1
-Yl) -acetic acid tert-butyl ester (6a)). Ethanol (1
. [2-benzyl-6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3,7-dioxo- [1,2] diazepan-1-in 5 mL).
Yl] -acetic acid tert-butyl ester (5a) (150 mg, 0.31 mmol) and hydrazine monohydrate (17.3 mg, 35 mmol) were placed in a chamber.
Stirred at room temperature for 6 hours. The solvent was removed under vacuum. The residue was treated with acetic acid (1.5 m
L) and stirred at room temperature for 30 minutes. The mixture is evaporated under vacuum.
And the resulting residue is dissolved in ethyl acetate (20 mL) and 5% Na _Two CO_ThreeAnd then with water. This aqueous solution was added to ethyl acetate (20 mL ×
Extracted in 2). The combined organic layers are_TwoSO_FourDried on and filtered
. The filtrate was evaporated under vacuum to dryness to give 107 mg (9 yield).
(8%) of the title compound.

[0202]

(Equation 5) (6-amino-3,7-dioxo-2-propyl- [1,2] diazepan-1-
Il) -acetic acid tert-butyl ester (6c) was prepared from 5c by the method used to prepare 6a to give 182 mg (69% yield) of the title compound.

[0203]

(Equation 6) ({2-benzyl-6-[(isoquinoline-1-carbonyl) -amino] -3,
Preparation of 7-dioxo- [1,2] diazepan-1-yl} -acetic acid tert-butyl ester (7a)). Isoquinoline (ioqu) in dichloromethane (5 mL)
inoline) -1-carbonic acid (173 mg, 1 mmol) at 0 ° C.
OBT (135 mg, 1 mmol) was added, followed by EDC (192 mg, 1 m
mol) was added. The mixture is stirred for 15 minutes and dichloromethane (5
(6-Amino-2-benzyl-3,7-dioxo- [1,2] diazepan-1-yl) -acetic acid tert-butyl ester (6a) (105 mg, 0.
30 mmol) was added. The reaction was stirred at 0 ° C. for 30 minutes, then at room temperature for 16 hours. The mixture was diluted with dichloromethane (50 mL) and washed with water (50 mL × 3). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under vacuum to give a pale yellow solid. This was purified by flash chromatography using dichloromethane / ethyl acetate (95/5 to 85/15) to give 128 mg (84% yield) of the title compound.

[0204]

(Equation 7) To prepare [6- (isoquinoline-1-carbonylamino) -3,7-dioxo-2-propyl- [1,2] diazepan-1-yl] -acetic acid tert-butyl ester (7b) to prepare 7a (6-Amino-3,7-dioxo-2-propyl- [1,2] diazepan-1
-Yl) -acetic acid tert-butyl ester (6c) and isoquinoline (io
quinoline) -1-carbonate to give 234 mg (86% yield) of the title compound.

[0205]

(Equation 8) [6- (4-allyloxy-3,5-dichloro-benzoylamino) -3,7-dioxo-2-propyl- [1,2] diazepan-1-yl] -acetic acid tert-butyl ester (7c) According to the method and chromatography used to prepare 7a, (6-amino-3,7-dioxo-2-propyl- [1,2] diazepan-1-yl) -acetic acid tert-butyl ester (6c) and Prepared from 3,5-dichloro-4-allyloxy-benzoyl acid and
g (72% yield) of the title compound were obtained.

[0206]

(Equation 9) (Isoquinoline-1-carboxylic acid} 1-benzyl-2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3,7-dioxo- [1,2] diazepan Preparation of -4-yl} -amide (10a)). {2-benzyl-6-[(isoquinoline-1-carbonyl) -amino] -3,
7-Dioxo- [1,2] diazepan-1-yl} -acetic acid tert-butyl ester (7a) (115 mg, 0.23 mmol) was added to dichloromethane (2 mL).
Stir in 20% trifluoroacetic acid (TFA) overnight. The solution was evaporated to give {2-benzyl-6-[(isoquinoline-1-carbonyl) -amino] -3,7-dioxo- [1,2] diazepan-1-yl} -acetic acid (8a). Obtained.

[0207]

(Equation 10) The acid (8a) was dissolved in dichloromethane (2 mL) followed by HOBT (77
mg, 0.57 mmol) and EDC (110 mg, 0.57 mmol) were added and stirred for 30 minutes. 1,3-dimethylbarbituric acid (DMBA)
(90 mg, 0.57 mmol) and Pd (PPh ₃ ) ₄ (66 mg, 0.05
7 mmol) for 30 minutes, (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) -carbamic acid allyl ester (9, antidiastereomer) in dichloromethane / DMF (3/1 mL) (166 mg, 0.
(57 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate (100 mL) and water (50
mL × 3), dried over Na ₂ SO ₄ , filtered and evaporated to give a pale yellow solid. This was added to dichloromethane / methanol (99.5 / 0.5
Purification by flash chromatography using ９８98.5 / 1.5) afforded 97.5 mg (67% yield) of the title compound.

[0208]

[Equation 11] Isoquinoline-1-carboxylic acid {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3,7-dioxo-1-propyl- [1,2] diazepane- 4-yl} -amide (10b)
Synthesized from the diastereomers of 7b and 9 by the method and chromatography used to prepare
203 mg, 67% yield, higher Rf) and antidiastereomer (93
mg, 31% yield, lower Rf).

[0209]

(Equation 12) 4-allyloxy-N- {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3,7-dioxo-1-propyl- [1,2] diazepan -4-yl} -3,5-dichloro-benzamide (10c) was synthesized from the diastereomers of 7c and 9 by the method used to prepare 10a and by chromatography to give the antidiadia of the title compound. Both stereomers (78 mg, 31% yield, lower Rf) and syndiastereomers (129 mg, 52% yield, higher Rf) were obtained.

[0210]

(Equation 13) (N- {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3,7-dioxo-1-propyl- [1,2
] Preparation of diazepan-4-yl} -3,5-dichloro-4-hydroxy-benzamide (10d)). 4-allyloxy-N in dichloromethane (15 mL)
-{2-[(2-Benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3,7-dioxo-1-propyl- [1,2] diazepan-4-yl} 3,5-dichloro - benzamide (10c, diastereomers) (103 mg, 0.16 mmol) to a solution of was added DMBA, followed by _{Pd (PPh 3) 4 (30mg} , 0.026mmol) was added to And stirred at room temperature for 7 hours. The reaction mixture was washed with water, dried over anhydrous Na ₂ SO _4, filtered, and purified by flash chromatography using dichloromethane / methanol (99.5 / 0.5 to 97/3), Both antidiastereomers of the title compound (18 mg, 18% yield, lower Rf) and syndiastereomers (48 mg, 50% yield, higher Rf) were obtained.

[0211]

[Equation 14] (3- (2- {2-benzyl-6-[(isoquinoline-1-carbonyl) -amino] -3,7-dioxo- [1,2] diazepan-1-yl} -acetylamino)
Preparation of 4-oxo-butyric acid (11a)). Isoquinoline-1-carboxylic acid {1-
Benzyl-2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3,7-dioxo- [1,2] diazepan-4-yl} -amide (10a, Diastereomer) (14 mg, 0.022 mm
ol) was stirred in a solution of 10% HCl (1.5 mL) and acetonitrile (1 mL) for 4 hours. The reaction mixture was diluted with water (30 mL) and washed twice with ether (30 mL). The aqueous solution was purged with nitrogen for 30 minutes, then cooled in dry ice and lyophilized overnight to give 10 mg (83% yield) of the title compound.

[0212]

(Equation 15) 3- (2- {6-[(isoquinoline-1-carbonyl) -amino] -3,7-dioxo-2-propyl- [1,2] diazepan-1-yl} -acetylamino)-
4-oxo-butyric acid (11b) was prepared according to the method used to prepare 11a, isoquinoline-1-carboxylic acid {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl). -Methyl] -3,7-dioxo-1-propyl- [1,2] diazepan-4-yl} -amide (10b, diastereomer) (95 mg, 0.16 mmol), 28 mg (yield) 35
%) Of the title compound.

[0213]

(Equation 16) 3- {2- [6- (3,5-dichloro-4-hydroxy-benzoylamino) -3,7-dioxo-2-propyl- [1,2] diazepan-1-yl] -acetylamino} -4 -Oxo-butyric acid (11c) was converted to N- {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -3 by the method used to prepare 11a. Prepared from 7,7-dioxo-1-propyl- [1,2] diazepan-4-yl} -3,5-dichloro-4-hydroxy-benzamide (10d, diastereomer) (30 mg, 0.05 mmol). This gave 19 mg (74% yield) of the title compound.

[0214]

[Equation 17] 3- {2- [6- (3,5-dichloro-4-hydroxy-benzoylamino) -3,7-dioxo-2-methyl- [1,2] diazepan-1-yl] -acetylamino} -4 -Oxo-butyric acid (11d) was prepared according to the method used to prepare 11c, but using iodomethane instead of allyl bromide.

Example 6 Compounds 19 and 20 were prepared as described below:

[0216]

Embedded image

[0219]

[Table 1]

[0218]

[Table 2] Preparation of 2- (N'-benzyloxycarbonyl-hydrazino) -propionic acid ethyl ester (12). To a solution of benzyl carbamate (665 mg, 4 mmol), triethylamine (1.11 mL) in dichloromethane (4 mL) was added 0
At 0 C, O-trifluoromethanesulfonyl-D-ethyl lactate was added dropwise. The solution was stirred at 0 ° C. for 15 minutes, then at room temperature for 16 hours. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL × 2), and 1% HCl (50 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure to give 570 mg (54% yield) of the title compound.

[0219]

(Equation 18) 5- [N'-benzyloxycarbonyl-N- (1-ethoxycarbonyl-ethyl) -hydrazino] -4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -5-oxo Benzyl pentanoate (13)
Prepared from-(N'-benzyloxycarbonyl-hydrazino) -propionic acid ethyl ester (12) and 2 by the method used for the preparation of 3 and chromatography, yielding 850 mg (64% yield) of the title compound. Obtained.

[0220]

[Equation 19] 2- [6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3,7-dioxo- [1,2] diazepan-1-yl] -propionic acid tert -Butyl ester (14) was converted to 5- [N′-benzyloxycarbonyl-N- (1-ethoxycarbonyl-ethyl) -hydrazino]
-4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-
Prepared from the 5-oxo-pentanoic acid benzyl ester (13) by using the method prepared for 4 and chromatography, 318 mg (64% yield)
The title compound was obtained.

[0221]

(Equation 20) 2- [6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2-methyl-3,7-dioxo- [1,2] diazepan-1-yl] -propionic acid Preparation of ethyl ester (15). 2- [6- in THF (8 mL)
(1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3,7
- dioxo - [1,2] diazepan-1-yl] - propionic acid tert- butyl ester (14) (314mg, 0.84mmol) , benzyltriethylammonium chloride _{(30mg, 0.13mmol), K 2} CO 3 (406mg ,
A mixture of 2.94 mmol) and iodomethane (360 mg, 2.53 mmol) was stirred at room temperature for 5 days. The mixture is diluted with dichloromethane (70 mL), washed three times with water, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure to give 296 mg (91% yield) of the title Was obtained as a mixture of diastereomers.

[0222]

(Equation 21) 2- (6-amino-2-methyl-3,7-dioxo- [1,2] diazepane-
1-yl) -propionic acid ethyl ester (16) was prepared according to the method used for the preparation of 6a, using 2- [6- (1,3-dioxo-1,3-dihydro-isoindole-
Prepared from 2-yl) -2-methyl-3,7-dioxo- [1,2] diazepan-1-yl] -propionic acid ethyl ester (15) to give 143 mg (73% yield) of the title compound. Obtained as a mixture of diastereomers.

[0223]

(Equation 22) 2- [6- (4-allyloxy-3,5-dichloro-benzoylamino) -2
-Methyl-3,7-dioxo [1,2] diazepan-1-yl] -propionic acid ethyl ester (17) was prepared according to the method used for the preparation of 7a and chromatography, to give 2- (6-amino-2- Prepared from methyl-3,7-dioxo- [1,2] diazepan-1-yl) -propionic acid ethyl ester (16) and 3,5-dichloro-4-allyloxy-benzoylic acid, 216 mg (80% yield) )
Was obtained as a mixture of diastereomers.

[0224]

(Equation 23) 2- [6- (4-allyloxy-3,5-dichloro-benzoylamino) -2
Preparation of -Methyl-3,7-dioxo- [1,2] diazepan-1-yl] -propionic acid (18). 2- [6- (4-allyloxy-3,5-dichloro-benzoylamino) -2-methyl-3,7-dioxo [1,2] diazepan-1-yl] -propionic acid ethyl ester (17) (216 mg) , 0.44 mmol) was stirred in 1N NaOH (2 mL) and MeOH (2 mL) at room temperature for 45 minutes. The mixture was diluted with water (30 mL) and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure to give 201 mg (99% yield) of the title compound.

[0225]

(Equation 24) N- {2- [1- (2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -ethyl] -1-methyl-3,7-dioxo- [1,
2] Preparation of diazepan-4-yl} -3,5-dichloro-4-hydroxy-benzamide (19). 2- [6- (4-allyloxy-3,5) in dichloromethane
-Dichloro-benzoylamino) -2-methyl-3,7-dioxo- [1,2]
Diazepan-1-yl] -propionic acid (18) (183 mg, 0.40 mmol
HOBT (65 mg, 0.48 mmol) was added to the solution of l), followed by ED
C (123 mg, 0.64 mmol) was added. The mixture is heated at 0 ° C. for 30
For 1 minute and then 1,3-dimethylbarbituric acid (DMBA) (75 mg,
0.48 mmol) and Pd (PPh _{3) 4} (60 mg, and 0.05 mmol), was placed for 30 minutes, in dichloromethane (2-benzyloxy-5-oxo - tetrahydro - furan-3-yl) carbamic acid allyl A solution of the ester (9, antidiastereomer) (140 mg, 0.48 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The second portion of DMBA (63 mg, 0
. 40 mmol) was added and the reaction mixture was continuously stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer
Dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give a pale yellow solid. This was purified by flash chromatography using dichloromethane / methanol (99/1 to 95/5) to give 70 mg (29% yield) of the title compound as a mixture of diastereomers.

[0226]

(Equation 25) 3- {2- [6- (3,5-dichloro-4-hydroxy-benzoylamino)
2-Methyl-3,7-dioxo- [1,2] diazepan-1-yl] -propionylamino} -4-oxo-butyric acid (20) was prepared according to the method used for the preparation of 11a by N- {2 -[1- (2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -ethyl] -1-methyl-3,7-dioxo- [
1,2] Diazepan-4-yl} -3,5-dichloro-4-hydroxy-benzamide (19) (28 mg, 0.046 mmol) and 17 mg (71
% Yield).

[0227]

(Equation 26) Example 7 Compound 27 was prepared as described below:

[0228]

Embedded image

[0229]

[Table 3] [6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)
Preparation of -7-oxo- [1,2] diazepan-1-yl] -acetic acid tert-butyl ester (21). [6- (1,3-dioxo-1,3) in THF (4 mL).
-Dihydro-isoindol-2-yl) -3,7-dioxo- [1,2] diazepan-1-yl] -acetic acid tert-butyl ester (4) (775 mg, 2.
(0 mmol) was added borane-THF complex in THF (1 M, 4 mL). The reaction was stirred at 0 ° C. for 30 minutes, then at room temperature for 3 hours. The mixture was diluted with ice-cold water (60 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a solid, which was flash chromatographed using hexane / ethyl acetate (95/5 to 70/30). Purification by chromatography afforded 585 mg (78% yield) of the title compound.

[0230]

[Equation 27] [6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)
Preparation of 2-methanesulfonyl-7-oxo- [1,2] diazepan-1-yl] acetic acid tert-butyl ester (22). [6- (1,3 in dichloromethane)
-Dioxo-1,3-dihydro-isoindol-2-yl) -7-oxo- [
1,2] diazepan-1-yl] -acetic acid tert-butyl ester (21) (1
55 mg, 0.42 mmol), triethylamine (0.5 mL) and 4-N
, N-Dimethylaminopyridine (DMAP) (101 mg, 0.50 mmol)
To the solution of was added methanesulfonyl chloride (95 mg, 0.83 mmol) dropwise. The mixture was stirred at 0 ° C. for 5 minutes and then at room temperature for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic solution was washed with water, then brine, dried over anhydrous Na ₂ SO _4, filtered, and purified by flash chromatography using dichloromethane / ethyl acetate (99 / 1-95 / 5) This gave 154 mg (82% yield) of the title compound.

[0231]

[Equation 28] (6-amino-2-methanesulfonyl-7-oxo- [1,2] diazepane-
1-yl) -acetic acid tert-butyl ester (23) was prepared according to the method used for the preparation of 6a, [6- (1,3-dioxo-1,3-dihydro-isoindole-
2-yl) -2-methanesulfonyl-7-oxo- [1,2] diazepan-1-
Yl] -acetic acid tert-butyl ester (22), 95 mg (89%
The title compound (yield) was obtained.

[0232]

(Equation 29) [6- (4-allyloxy-3,5-dichloro-benzoylamino) -2-methanesulfonyl-7-oxo- [1,2] diazepan-1-yl] -acetic acid ter
The t-butyl ester (24) was prepared according to the method used for the preparation of 7c and by chromatography, (6-amino-2-methanesulfonyl-7-oxo- [1,2] diazepan-1-yl) -tert-butyl acetate. Esters (23) and 3,5-
Prepared from dichloro-4-allyloxybenzoylic acid to give 193 mg (87% yield) of the title compound.

[0233]

[Equation 30] [6- (4-allyloxy-3,5-dichloro-benzoylamino) -2-methanesulfonyl-7-oxo- [1,2] diazepan-1-yl] -acetic acid (25
) Was converted to [6- (4-allyloxy-3,5-) by the method used to prepare 8a.
Dichloro-benzoylamino) -2-methanesulfonyl-7-oxo- [1,2
[Diazepan-1-yl] -acetic acid tert-butyl ester (24) to give 173 mg (100% yield) of the title compound.

[0234]

(Equation 31) 4-allyloxy-N- {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -1-methanesulfonyl-
3-oxo- [1,2] diazepan-4-yl} -3,5-dichloro-benzamide (26a) was prepared according to the method used for the preparation of 10a and by chromatography, [6- (4-allyloxy-3, 5-dichloro-benzoylamino) -2-
Methanesulfonyl-7-oxo- [1,2] diazepan-1-yl] -acetic acid (2
Prepared from 5) and (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl) carbamic acid allyl ester (9, a mixture of diastereomers), affording 178 mg (74% yield) of the title compound. Obtained as a mixture of diastereomers.

[0235]

(Equation 32) N- {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3
-Ylcarbamoyl) -methyl] -1-methanesulfonyl-3-oxo- [1,
2] Preparation of diazepan-4-yl} -3,5-dichloro-4-hydroxy-benzamide (26b). 4-allyloxy-N- in dichloromethane (6 mL)
{2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -1-methanesulfonyl-3-oxo- [1,2] diazepan-4-yl} -3, 5-Dichloro-benzamide (26a) (178m
g, 0.26 mmol) with DMBA (45 mg, 0.29 mmol) and P
Treatment with d (PPh ₃ ) ₄ (20 mg, 0.017 mmol) at room temperature for 16 hours. The mixture was diluted with dichloromethane (40 mL) and washed three times with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give a pale yellow solid which was combined with dichloromethane / methanol (99.2 / 0.8-97.5 /
Purification by flash chromatography using 2.5) to give 78 mg (
47% yield of the syn diastereomer of the title compound (high Rf) and 59m
g (35% yield) of antidiastereomer (low Rf) was obtained.

[0236]

[Equation 33] 3- {2- [6- (3,5-dichloro-4-hydroxy-benzoylamino)
Preparation of -2-methanesulfonyl-7-oxo- [1,2] diazepan-1-yl] -acetylamino} -4-oxo-butyric acid (27). N- {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -methyl] -1-methanesulfonyl-3-oxo- [1,2] diazepan-4-yl}
3,5-dichloro-4-hydroxy - benzamide (26b), and stirred CH ₃ CN (0.5mL) and 2N HCl (1 mL) in 7 minutes. The solution was concentrated under reduced pressure to half volume and extracted with ether (2 mL x 4). Dilute the combined ether layers with ethyl acetate / hexane (1/9, 3 mL),
Washed with 1M Na ₂ CO ₃ (2 mL). The aqueous solution was diluted with ethyl acetate / hexane (1
/ 9, 2 mL x 2), acidified with 6N HCCl until pH was about 3, and extracted with ethyl acetate (1.5 mL x 3). The combined extracts were dried over anhydrous Na ₂ SO _4, filtered, and dried and concentrated under reduced pressure to give the title compound 20 mg (47% yield).

[0237]

(Equation 34) * Analytical HPLC conditions: Column: Microsorb ^™ C-18, 5μ, 4.6 x 150 mm (unless otherwise noted).

Solvent A: 0.1% TFA / 1% MeCN / 98.9% water Solvent B: 0.1% TFA / 99.9% MeCN Gradient: 20 minutes from A to B at a flow rate of 1 mL / min.

(Example 8)

[0240]

[Table 4] Within the scope of the compounds of the present invention, they can inhibit caspases, especially ICE, in vitro and can be delivered orally to mammals; The clinical utility for the treatment of gamma-mediated diseases is clear.

Having described a number of embodiments of the present invention, it will be apparent that we can vary our basic constructs to provide other embodiments that utilize the products and processes of the present invention. It is.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] October 8, 1999 (1999.10.8)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0174

[Correction method] Change

[Correction contents]

Experimental Procedures Prepare a series of initial dilutions of test compounds in DMSO or ethanol, followed by RPMI-10% FBS medium (2 mM L-glutamine, 10 mM HEPE
S, containing 50 U and 50 μg / ml pen / strep, respectively) to give the drug at 4 times (4 ×) the final test concentration containing 0.4% DMSO or 0.4% ethanol. . The final concentration of DMSO is 0.1% for all drug dilutions. A concentration titration that takes into account the apparent K _i for the test compound as determined in the ICE inhibition assay is generally used as an initial compound screen.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 1/18 A61P 1/18 3/10 3/10 5/00 5/00 7/04 7/04 7 / 06 7/06 9/02 9/02 9/10 9/10 11/00 11/00 11/06 11/06 13/12 13/12 17/00 17/00 17/06 17/06 17/14 17/14 19/02 19/02 19/08 19/08 19/10 19/10 21/04 21/04 25/00 25/00 25/16 25/16 25/28 25/28 29/00 29 / 00 101 101 31/04 31/04 31/12 31/12 35/00 35/00 35/02 35/02 37/06 37/06 43/00 107 43/00 107 111 111 111 C07D 401/12 C07D 401 / 12 401/14 401/14 403/04 403/04 405/12 405/12 405/14 405/14 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, G , GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant 130 Waverly Street, Ca Mridge, Massachus etts 02139-4242, U.S. Pat. S. A. (72) Inventor Charifson, Paul United States Massachusetts 01701, Framingham, Dartmouth Drive 7 (72) Inventor Loafer, David Jay. United States Massachusetts 01775, Stowe, Taylor Road 254 (72) Inventor Murican, Michael Dee. United States Massachusetts 02194, Needham, Parker Road 110 F-term (reference) 4C063 AA01 AA03 BB09 CC36 CC73 DD15 DD36 EE01 4C086 AA01 AA02 AA03 BC53 GA02 GA07 MA01 MA04 NA14 ZA02 ZA16 ZA36 ZA51 ZA55 ZAZ ZA ZA ZA ZA Z ZB11 ZB15 ZB26 ZB27 ZB33 ZB35 ZC06 ZC35 ZC39 ZC55

Claims (23)

[Claims] 1. A compound represented by the following formula (I):Where Y is: embedded image m is 0 or 1; W is -CH_Two-, -C (O)-, S (O)_Two-Or -S (O)-; X is -C (H)-, -C (R⁸)-OrZ is -CH_Two-, -O-, -S-, or -N (R¹)-, Where Z
Is -N (R¹)-, W is -C (O)-, -S (O)_Two-Or -S (O
)-; Each R₁Is independently -H, -C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸ , -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, -A
I'm Luquil; R^TwoIs -C (O) R⁸, -C (O) C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸, -C (O) OR⁸, -C (O) N (H) R⁸, -S (O)_TwoN (H) -R⁸ , -S (O) N (H) -R⁸, -C (O) C (O) N (H) R⁸, -C (O) CH
= CHR⁸, -C (O) CH_TwoOR⁸, -C (O) CH_TwoN (H) R⁸, -C (O) N (R⁸)_Two, -S (O)_TwoN (R⁸)_Two, -S (O) N (R⁸)_Two, -C (O) C (O) N (R⁸)_Two, -C (O) CH_TwoN (R⁸)_Two, -CH_Two-R⁸, -CH_Two−Arche
Nil-R⁸Or -CH_Two-Alkynyl-R⁸R^ThreeIs -H, -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, An alkyl, or an amino acid side chain; each R^FourIs independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN
, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -Alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (alkyl)_Two, -C (O) N (H) alkyl, -C (O) N (alkyl)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl, -C (O) alkyl, -CH_TwoNH_Two, -CH_TwoN (H) alkyl, -CH_TwoN (alkyl)_TwoOr —N (H) C (O) Oalkyl; R^FiveIs -OH, -OR⁸, -N (H) OH, or -N (H) SO_TwoR⁸Is
R⁶Is -H, -CH_TwoOR⁹, -CH_TwoSR^Ten, -CH_TwoN (H) R⁹, -CH_Two N (R⁹) R¹¹, -C (H) N_Two, -CH_TwoF, -CH_TwoCl, -CH_TwoBr, -CH_TwoI, -C (O) N (R¹¹)_Two, -R¹³Or -R¹⁴And each R⁸Is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocycle, -alkylcycloalkyl-alkylaryl, -al
R is a heteroalkyl or a heteroalkyl ring;⁹Is -H, -C (O) aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (O) alkylheteroaryl, -alkylaryl,
-Alkylheteroaryl, -aryl, -heteroaryl, or -P (O)
(R^Fifteen)_TwoR^TenIs -alkylaryl or -alkylheteroaryl; each R¹¹Is independently -H, -alkyl, -aryl, -heteroaryl,-
R is cycloalkyl, -alkylaryl or -alkylheteroaryl;¹³Is -alkylaryl or -alkylheteroaryl; R¹⁴Is the following: Here, Q is —O— or —S—, and any hydrogen atom of (i)
Depending on -R¹⁷And (ii), (iii), and (i)
The optional hydrogen atom in v) may be, optionally, -R¹⁷, -R¹⁸Or -alkyl-R ¹⁸ Each R^FifteenIs independently -H, -OH, -alkyl, -aryl, -heteroally
, -Cycloalkyl, -alkylaryl, -alkylheteroaryl,-
O alkyl, -O aryl, -O heteroaryl, -O alkylaryl or
—O alkylheteroaryl; each R¹⁷Is independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -SO_TwoNH_Two, -C (O) H, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (A
Lequil)_Two, -CO_TwoAlkyl, -C (O) N (H) alkyl, -C (O) N (A
Lequil)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S (O)_TwoN (H) alkyl, -S
(O) N (H) alkyl, -S (O)_TwoN (alkyl)_Two, -S (O) N (Alky
Le)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl or -C
(O) alkyl; each R¹⁸Is independently -aryl, -heteroaryl, -alkylaryl,
-Alkylheteroaryl, -O-aryl, -O-heteroaryl, -O-a
Alkylaryl, -O-alkylheteroaryl, -N (H) aryl, -N (
Aryl)_Two, -N (H) heteroaryl, -N (heteroaryl)_Two, -N (H
) Alkylaryl, -N (alkylaryl)_Two, -N (H) alkylheteroaryl, -N (alkylheteroaryl)_Two, -S-aryl, -S-heteroaryl, -S-alkylaryl, -S-alkylheteroaryl, -C (O
) Aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (
O) alkylheteroaryl, -CO_TwoAryl, -CO_TwoHeteroaryl, -C
O_TwoAlkylaryl, -CO_TwoAlkylheteroaryl, -C (O) N (H)
Reel, -C (O) N (aryl)_Two, -C (O) N (H) heteroaryl, -C (O) N (heteroaryl)_Two, -C (O) N (H) alkylaryl, -C (O) N (alkylaryl)_Two, -C (O) N (H) alkylheteroaryl, -C (O) N (alkylheteroaryl)_Two, -S (O)_Two-Aryl, -S (
O) -aryl, -S (O)_Two-Heteroaryl, -S (O) -heteroaryl, -S (O)_Two-Alkylaryl, -S (O) -alkylaryl, -S (O)_Two-Alkylheteroaryl, -S (O) -alkylheteroaryl, -S (O)_TwoN (H) -aryl, -S (O) N (H) -aryl, -S (O)_TwoNH-
Heteroaryl, -S (O) NH-heteroaryl, -S (O)_TwoN (H) -alkylaryl, -S (O) N (H) -alkylaryl, -S (O)_TwoN (H) -alkylheteroaryl, -S (O) N (H) -alkylheteroaryl,
-S (O)_TwoN (aryl)_Two, -S (O) N (aryl)_Two, -S (O)_TwoN (he
Terrorist aryl)_Two, -S (O) N (heteroaryl)_Two, -S (O)_TwoN (alkylaryl)_Two, -S (O) N (alkylaryl)_Two, -S (O)_TwoN (alkylheteroaryl)_Two, -S (O) N (alkylheteroaryl)_Two, -N (H)
C (O) N (H) aryl, -N (H) C (O) N (H) heteroaryl, -N
(H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) alkyl
Ruheteroaryl, -N (H) C (O) N (aryl)_Two, -N (H) C (O) N (heteroaryl)_Two, -N (H) C (O) N (alkylaryl)_TwoOr-
N (H) C (O) N (alkylheteroaryl)_TwoAnd each R^{twenty one}Is independently -aryl, -heteroaryl, -cycloaryl, or
Or a heterocyclic ring, wherein a hydrogen atom bonded to any carbon atom is
By the way, R^FourA hydrogen atom which is substituted by and is attached to any nitrogen atom^TwoThe compound has been replaced by 2. A compound represented by the following formula (I):Where Y is: embedded image m is 0 or 1; W is -CH_Two-, -C (O)-, -S (O)_Two-Or -S (O)-;
X is -C (H)-, -C (R⁸)-OrZ is -CH_Two-, -O-, -S-, or -N (R¹)-, Where Z is
−N (R¹)-, Then W is -C (O)-, -S (O)_Two-; Or -S (
O)-; each R₁Is independently -H, -C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸ , -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, -A
I'm Luquil; R^TwoIs -C (O) R⁸, -C (O) C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸, -C (O) OR⁸, -C (O) N (H) R⁸, -S (O)_TwoN (H) R⁸, -S (O) N (H) R⁸, -C (O) C (O) N (H) R⁸, -C (O) CH = C
HR⁸, -C (O) CH_TwoOR⁸, -C (O) CH_TwoN (H) R⁸, -C (O) N (R⁸)_Two, -S (O)_TwoN (R⁸)_Two, -S (O) N (R⁸)_Two, -C (O) C (O) N (R⁸)_Two, -C (O) CH_TwoN (R⁸)_Two, -CH_TwoR⁸, -CH_Two-Alkenyl-
R⁸Or -CH_Two-Alkynyl-R⁸R^ThreeIs -H, -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, An alkyl, or an amino acid side chain; each R^FourIs independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN
, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -Alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (alkyl)_Two, -C (O) N (H) alkyl, -C (O) N (alkyl)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl, -C (O) alkyl, -CH_TwoNH_Two, -CH_TwoN (H) alkyl, -CH_TwoN (alkyl)_TwoOr —N (H) C (O) Oalkyl; R⁶Is -H, -CH_TwoOR⁹, -CH_TwoSR^Ten, -CH_TwoN (H) R⁹, -CH_Two N (R⁹) R¹¹, -C (H) N_Two, -CH_TwoF, -CH_TwoCl, -CH_TwoBr, -CH_TwoI, -C (O) N (R¹¹)_Two, -R¹³Or -R¹⁴R⁷Is -alkyl, -C (O) cycloalkyl, -C (O) alkenyl, -C (O) alkynyl, -C (O) alkylaryl, -C (O) alkylhetero.
An aryl, —C (O) heterocycle, or —C (O) alkylheterocycle;⁸Is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocycle, -alkylcycloalkyl-alkylaryl, -al
R is a heteroalkyl or an alkylalkyl heterocycle;⁹Is -H, -C (O) aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (O) alkylheteroaryl, -alkylaryl,
-Alkylheteroaryl, -aryl, -heteroaryl or -P (O) (
R^Fifteen)_TwoR^TenIs -alkylaryl or -alkylheteroaryl; each R¹¹Is independently -H, -alkyl, -aryl, -heteroaryl,-
R is cycloalkyl, -alkylaryl or -alkylheteroaryl;¹³Is -alkylaryl or -alkylheteroaryl; R¹⁴Is the following: Here, Q is —O— or —S—, and any hydrogen atom of (i)
Depending on -R¹⁷And (ii), (iii), and (i)
The optional hydrogen atom in v) may be, optionally, -R¹⁷, -R¹⁸Or -alkyl-R ¹⁸ Each R^FifteenIs independently -H, -OH, -alkyl, -aryl, -heteroally
, -Cycloalkyl, -alkylaryl, -alkylheteroaryl,-
O alkyl, -O aryl, -O heteroaryl, -O alkylaryl or
—O alkylheteroaryl; each R¹⁷Is independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -SO_TwoNH_Two, -C (O) H, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (A
Lequil)_Two, -CO_TwoAlkyl, -C (O) N (H) alkyl, -C (O) N (A
Lequil)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S (O)_TwoN (H) alkyl, -S
(O) N (H) alkyl, -S (O)_TwoN (alkyl)_Two, -S (O) N (Alky
Le)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl or -C
(O) alkyl; each R¹⁸Is independently -aryl, -heteroaryl, -alkylaryl,
-Alkylheteroaryl, -O-aryl, -O-heteroaryl, -O-a
Alkylaryl, -O-alkylheteroaryl, -N (H) aryl, -N (
Aryl)_Two, -N (H) heteroaryl, -N (heteroaryl)_Two, -N (H
) Alkylaryl, -N (alkylaryl)_Two, -N (H) alkylheteroaryl, -N (alkylheteroaryl)_Two, -S-aryl, -S-heteroaryl, -S-alkylaryl, -S-alkylheteroaryl, -C (O
) Aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (
O) alkylheteroaryl, -CO_TwoAryl, -CO_TwoHeteroaryl, -C
O_TwoAlkylaryl, -CO_TwoAlkylheteroaryl, -C (O) N (H)
Reel, -C (O) N (aryl)_Two, -C (O) N (H) heteroaryl, -C (O) N (heteroaryl)_Two, -C (O) N (H) alkylaryl, -C (O) N (alkylaryl)_Two, -C (O) N (H) alkylheteroaryl, -C (O) N (alkylheteroaryl)_Two, -S (O)_Two-Aryl, -S (
O) -aryl, -S (O)_Two-Heteroaryl, -S (O) -heteroaryl, -S (O)_Two-Alkylaryl, -S (O) -alkylaryl, -S (O)_Two-Alkylheteroaryl, -S (O) -alkylheteroaryl, -S (O)_TwoN (H) -aryl, -S (O) N (H) -aryl, -S (O)_TwoNH-
Heteroaryl, -S (O) NH-heteroaryl, -S (O)_TwoN (H) -alkylaryl, -S (O) N (H) -alkylaryl, -S (O)_TwoN (H) -alkylheteroaryl, -S (O) N (H) -alkylheteroaryl,
-S (O)_TwoN (aryl)_Two, -S (O) N (aryl)_Two, -S (O)_TwoN (he
Terrorist aryl)_Two, -S (O) N (heteroaryl)_Two, -S (O)_TwoN (alkylaryl)_Two, -S (O) N (alkylaryl)_Two, -S (O)_TwoN (alkylheteroaryl)_Two, -S (O) N (alkylheteroaryl)_Two, -N (H)
C (O) N (H) aryl, -N (H) C (O) N (H) heteroaryl, -N
(H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) alkyl
Ruheteroaryl, -N (H) C (O) N (aryl)_Two, -N (H) C (O) N (heteroaryl)_Two, -N (H) C (O) N (alkylaryl)_TwoOr-
N (H) C (O) N (alkylheteroaryl)_TwoAnd each R^{twenty one}Is independently -aryl, -heteroaryl, -cycloaryl, or
Or a heterocyclic ring, wherein a hydrogen atom bonded to any carbon atom is
By the way, R^FourA hydrogen atom which is substituted by and is attached to any nitrogen atom^TwoThe compound has been replaced by 3. A compound represented by the following formula (II):Where Y is: embedded image C is an aryl or heteroaryl ring, wherein C is
Optional hydrogen atom is optionally -R^FourM is 0 or 1; W is -CH_Two-, -C (O)-, -S (O)_Two-Or -S (O)-;
X is -C (H)-, -C (R⁸)-OrAnd each R₁Is independently -H, -C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸ , -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, -A
I'm Luquil; R^TwoIs -C (O) R⁸, -C (O) C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸, -C (O) OR⁸, -C (O) N (H) R⁸, -S (O)_TwoN (H) -R⁸ , -S (O) N (H) -R⁸, -C (O) C (O) N (H) R⁸, -C (O) CH
= CHR⁸, -C (O) CH_TwoOR⁸, -C (O) CH_TwoN (H) R⁸, -C (O) N (R⁸)_Two, -S (O)_TwoN (R⁸)_Two, -S (O) N (R⁸)_Two, -C (O) C (O) N (R⁸)_Two, -C (O) CH_TwoN (R⁸)_Two, -CH_TwoR⁸, -CH_Two-Alkene
Le-R⁸Or -CH_Two-Alkynyl-R⁸R^ThreeIs -H, -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, An alkyl, or an amino acid side chain; each R^FourIs independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN
, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -Alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (alkyl)_Two, -C (O) N (H) alkyl, -C (O) N (alkyl)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl, -C (O) alkyl, -CH_TwoNH_Two, -CH_TwoN (H) alkyl, -CH_TwoN (alkyl)_TwoOr —N (H) C (O) Oalkyl; R^FiveIs -OH, -OR⁸, -N (H) OH, or -N (H) SO_TwoR⁸Is
R⁶Is -H, -CH_TwoOR⁹, -CH_TwoSR^Ten, -CH_TwoN (H) R⁹, -CH_Two N (R⁹) R¹¹, -C (H) N_Two, -CH_TwoF, -CH_TwoCl, -CH_TwoBr, -CH_TwoI, -C (O) N (R¹¹)_Two, -R¹³Or -R¹⁴And each R⁸Is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocycle, -alkylcycloalkyl-alkylaryl, -al
R is a heteroalkyl or an alkylalkyl heterocycle;⁹Is -H, -C (O) aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (O) alkylheteroaryl, -alkylaryl,
-Alkylheteroaryl, -aryl, -heteroaryl or -P (O) (
R^Fifteen)_TwoR^TenIs -alkylaryl or -alkylheteroaryl; each R¹¹Is independently -H, -alkyl, -aryl, -heteroaryl,-
R is cycloalkyl, -alkylaryl or -alkylheteroaryl;¹³Is -alkylaryl or -alkylheteroaryl; R¹⁴Is the following: Here, Q is —O— or —S—, and any hydrogen atom of (i)
Depending on -R¹⁷And (ii), (iii), and (i)
The optional hydrogen atom in v) may be, optionally, -R¹⁷, -R¹⁸Or -alkyl-R ¹⁸ Each R^FifteenIs independently -H, -OH, -alkyl, -aryl, -heteroally
, -Cycloalkyl, -alkylaryl, -alkylheteroaryl,-
O alkyl, -O aryl, -O heteroaryl, -O alkylaryl or
—O alkylheteroaryl; each R¹⁷Is independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -SO_TwoNH_Two, -C (O) H, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (A
Lequil)_Two, -CO_TwoAlkyl, -C (O) N (H) alkyl, -C (O) N (A
Lequil)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S (O)_TwoN (H) alkyl, -S
(O) N (H) alkyl, -S (O)_TwoN (alkyl)_Two, -S (O) N (Alky
Le)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl or -C
(O) alkyl; each R¹⁸Is independently -aryl, -heteroaryl, -alkylaryl,
-Alkylheteroaryl, -O-aryl, -O-heteroaryl, -O-a
Alkylaryl, -O-alkylheteroaryl, -N (H) aryl, -N (
Aryl)_Two, -N (H) heteroaryl, -N (heteroaryl)_Two, -N (H
) Alkylaryl, -N (alkylaryl)_Two, -N (H) alkylheteroaryl, -N (alkylheteroaryl)_Two, -S-aryl, -S-heteroaryl, -S-alkylaryl, -S-alkylheteroaryl, -C (O
) Aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (
O) alkylheteroaryl, -CO_TwoAryl, -CO_TwoHeteroaryl, -C
O_TwoAlkylaryl, -CO_TwoAlkylheteroaryl, -C (O) N (H)
Reel, -C (O) N (aryl)_Two, -C (O) N (H) heteroaryl, -C (O) N (heteroaryl)_Two, -C (O) N (H) alkylaryl, -C (O) N (alkylaryl)_Two, -C (O) N (H) alkylheteroaryl, -C (O) N (alkylheteroaryl)_Two, -S (O)_Two-Aryl, -S (
O) -aryl, -S (O)_Two-Heteroaryl, -S (O) -heteroaryl, -S (O)_Two-Alkylaryl, -S (O) -alkylaryl, -S (O)_Two-Alkylheteroaryl, -S (O) -alkylheteroaryl, -S (O)_TwoN (H) -aryl, -S (O) N (H) -aryl, -S (O)_TwoNH-
Heteroaryl, -S (O) NH-heteroaryl, -S (O)_TwoN (H) -alkylaryl, -S (O) N (H) -alkylaryl, -S (O)_TwoN (H) -alkylheteroaryl, -S (O) N (H) -alkylheteroaryl,
-S (O)_TwoN (aryl)_Two, -S (O) N (aryl)_Two, -S (O)_TwoN (he
Terrorist aryl)_Two, -S (O) N (heteroaryl)_Two, -S (O)_TwoN (alkylaryl)_Two, -S (O) N (alkylaryl)_Two, -S (O)_TwoN (alkylheteroaryl)_Two, -S (O) N (alkylheteroaryl)_Two, -N (H)
C (O) N (H) aryl, -N (H) C (O) N (H) heteroaryl, -N
(H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) alkyl
Ruheteroaryl, -N (H) C (O) N (aryl)_Two, -N (H) C (O) N (heteroaryl)_Two, -N (H) C (O) N (alkylaryl)_TwoOr-
N (H) C (O) N (alkylheteroaryl)_TwoAnd each R^{twenty one}Is independently -aryl, -heteroaryl, -cycloaryl, or
Or a heterocyclic ring, wherein a hydrogen atom bonded to any carbon atom is
By the way, R^FourA hydrogen atom which is substituted by and is attached to any nitrogen atom^TwoThe compound has been replaced by 4. A compound represented by the following formula (II):Where Y is: embedded image C is an aryl or heteroaryl ring, wherein C is
Optional hydrogen atom is optionally -R^FourM is 0 or 1; W is -CH_Two-, -C (O)-, -S (O)_Two-Or -S (O)-;
X is -C (H)-, -C (R⁸)-OrAnd each R₁Is independently -H, -C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸ , -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, -A
I'm Luquil; R^TwoIs -C (O) R⁸, -C (O) C (O) R⁸, -S (O)_TwoR⁸, -S (O) R⁸, -C (O) OR⁸, -C (O) N (H) R⁸, -S (O)_TwoN (H) -R⁸ , -S (O) N (H) -R⁸, -C (O) C (O) N (H) R⁸, -C (O) CH
= CHR⁸, -C (O) CH_TwoOR⁸, -C (O) CH_TwoN (H) R⁸, -C (O) N (R⁸)_Two, -S (O)_TwoN (R⁸)_Two, -S (O) N (R⁸)_Two, -C (O) C (O) N (R⁸)_Two, -C (O) CH_TwoN (R⁸)_Two, -CH_TwoR⁸, -CH_Two-Alkene
Le-R⁸Or -CH_Two-Alkynyl-R⁸R^ThreeIs -H, -R^{twenty one}, -Alkyl-R^{twenty one}, -Alkenyl-R^{twenty one}, -Alkynyl-R^{twenty one}, An alkyl, or an amino acid side chain; each R^FourIs independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN
, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -Alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (alkyl)_Two, -C (O) N (H) alkyl, -C (O) N (alkyl)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl, -C (O) alkyl, -CH_TwoNH_Two, -CH_TwoN (H) alkyl, -CH_TwoN (alkyl)_TwoOr —N (H) C (O) Oalkyl; R⁶Is -H, -CH_TwoOR⁹, -CH_TwoSR^Ten, -CH_TwoN (H) R⁹, -CH_Two N (R⁹) R¹¹, -C (H) N_Two, -CH_TwoF, -CH_TwoCl, -CH_TwoBr, -CH_TwoI, -C (O) N (R¹¹)_Two, -R¹³Or -R¹⁴R⁷Is -C (O) alkyl, -C (O) cycloalkyl, -C (O) alkenyl, -C (O) alkenyl, -C (O) alkynyl, -C (O) alkyl
Reel, -C (O) alkylheteroaryl, -C (O) heterocycle, or -C
(O) an alkyl heterocycle; each R⁸Is independently -alkyl, -cycloalkyl, -aryl, -heteroaryl, -heterocycle, -alkylcycloalkyl-alkylaryl, -al
R is a heteroalkyl or an alkylalkyl heterocycle;⁹Is -H, -C (O) aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (O) alkylheteroaryl, -alkylaryl,
-Alkylheteroaryl, -aryl, -heteroaryl or -P (O) (
R^Fifteen)_TwoR^TenIs -alkylaryl or -alkylheteroaryl; each R¹¹Is independently -H, -alkyl, -aryl, -heteroaryl,-
R is cycloalkyl, -alkylaryl or -alkylheteroaryl;¹³Is -alkylaryl or -alkylheteroaryl; R¹⁴Is the following: Here, Q is —O— or —S—, and any hydrogen atom of (i)
Depending on -R¹⁷And (ii), (iii), and (i)
The optional hydrogen atom in v) may be, optionally, -R¹⁷, -R¹⁸Or -alkyl-R ¹⁸ Each R^FifteenIs independently -H, -OH, alkyl, aryl, heteroaryl,
Cycloalkyl, alkylaryl, alkylheteroaryl, -Oalkyl,
-Oaryl, -Oheteroaryl, -Oalkylaryl or -Oalkyl
Heteroaryl; each R¹⁷Is independently -OH, -F, -Cl, -Br, -I, -NO_Two, -CN, -NH_Two, -CO_TwoH, -C (O) NH_Two, -N (H) C (O) H, -N (H) C (O) NH_Two, -SO_TwoNH_Two, -C (O) H, -alkyl, -cycloalkyl, -perfluoroalkyl, -O-alkyl, -N (H) alkyl, -N (A
Lequil)_Two, -CO_TwoAlkyl, -C (O) N (H) alkyl, -C (O) N (A
Lequil)_Two, -N (H) C (O) alkyl, -N (H) C (O) N (H) alkyl, -N (H) C (O) N (alkyl)_Two, -S (O)_TwoN (H) alkyl, -S
(O) N (H) alkyl, -S (O)_TwoN (alkyl)_Two, -S (O) N (Alky
Le)_Two, -S-alkyl, -S (O)_TwoAlkyl, -S (O) alkyl or -C
(O) alkyl; each R¹⁸Is independently -aryl, -heteroaryl, -alkylaryl,
-Alkylheteroaryl, -O-aryl, -O-heteroaryl, -O-a
Alkylaryl, -O-alkylheteroaryl, -N (H) aryl, -N (
Aryl)_Two, -N (H) heteroaryl, -N (heteroaryl)_Two, -N (H
) Alkylaryl, -N (alkylaryl)_Two, -N (H) alkylheteroaryl, -N (alkylheteroaryl)_Two, -S-aryl, -S-heteroaryl, -S-alkylaryl, -S-alkylheteroaryl, -C (O
) Aryl, -C (O) heteroaryl, -C (O) alkylaryl, -C (
O) alkylheteroaryl, -CO_TwoAryl, -CO_TwoHeteroaryl, -C
O_TwoAlkylaryl, -CO_TwoAlkylheteroaryl, -C (O) N (H)
Reel, -C (O) N (aryl)_Two, -C (O) N (H) heteroaryl, -C (O) N (heteroaryl)_Two, -C (O) N (H) alkylaryl, -C (O) N (alkylaryl)_Two, -C (O) N (H) alkylheteroaryl, -C (O) N (alkylheteroaryl)_Two, -S (O)_Two-Aryl, -S (
O) -aryl, -S (O)_Two-Heteroaryl, -S (O) -heteroaryl, -S (O)_Two-Alkylaryl, -S (O) -alkylaryl, -S (O)_Two-Alkylheteroaryl, -S (O) -alkylheteroaryl, -S (O)_TwoN (H) -aryl, -S (O) N (H) -aryl, -S (O)_TwoNH-
Heteroaryl, -S (O) NH-heteroaryl, -S (O)_TwoN (H) -alkylaryl, -S (O) N (H) -alkylaryl, -S (O)_TwoN (H) -alkylheteroaryl, -S (O) N (H) -alkylheteroaryl,
-S (O)_TwoN (aryl)_Two, -S (O) N (aryl)_Two, -S (O)_TwoN (he
Terrorist aryl)_Two, -S (O) N (heteroaryl)_Two, -S (O)_TwoN (alkylaryl)_Two, -S (O) N (alkylaryl)_Two, -S (O)_TwoN (alkylheteroaryl)_Two, -S (O) N (alkylheteroaryl)_Two, -N (H)
C (O) N (H) aryl, -N (H) C (O) N (H) heteroaryl, -N
(H) C (O) N (H) alkylaryl, -N (H) C (O) N (H) alkyl
Ruheteroaryl, -N (H) C (O) N (aryl)_Two, -N (H) C (O) N (heteroaryl)_Two, -N (H) C (O) N (alkylaryl)_TwoOr-
N (H) C (O) N (alkylheteroaryl)_TwoAnd each R^{twenty one}Is independently -aryl, -heteroaryl, -cycloaryl, or
Or a heterocyclic ring, wherein a hydrogen atom bonded to any carbon atom is
By the way, R^FourA hydrogen atom which is substituted by and is attached to any nitrogen atom^TwoThe compound has been replaced by 5. The compound according to claim 1, wherein R ¹ is aryl, heteroaryl, alkyl, alkylaryl, or alkylheteroaryl. 6. The compound according to claim 5, wherein R ¹ is: A compound that is 7. The compound according to claim 1, wherein R ² is: A compound that is 8. The compound of claim 1, wherein R ³ is an amino acid side chain, aryl, heteroaryl, alkyl, alkylaryl, or alkylheteroaryl. Compound. 9. The compound according to claim 8, wherein R ³ is: A compound that is 10. The compound according to any one of claims 1 to 4, wherein R ⁶ is —H. 11. The compound according to claim 2 or 4, wherein R ⁸ is alkyl, alkylcycloalkyl, aryl, alkylaryl, or alkylheterocycle. 12. The compound according to claim 11, wherein Y is: And V is: A compound that is 13. The compound according to claim 1, wherein: A compound selected from the group consisting of: 14. The compound according to claim 2, wherein: A compound selected from the group consisting of: 15. A pharmaceutical composition comprising: a) any one of claims 1 to 14;
And b) a pharmaceutically acceptable carrier, adjuvant or vehicle. 16. A method for treating or preventing a disease, wherein said disease is in a patient: IL-1 mediated disease, apoptosis mediated disease, inflammatory disease, autoimmune disease, destructive bone. Disorders, proliferative disorders, infectious diseases, degenerative diseases, necrotic diseases, excessive drinking alcohol diseases, virus-borne diseases, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma,
Adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, Autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, graft-versus-host disease, osteoporosis, multiple myeloma-related bone disorders, acute Myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, bacillary dysentery, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal atrophy , Multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia,
A disease selected from the following: neurological damage due to seizure, ulcerative colitis, traumatic brain injury, organ transplant rejection, hepatitis B, hepatitis C, hepatitis G, yellow fever, dengue or Japanese encephalitis, 16. A method comprising administering to the patient a compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15. 17. The method of claim 16, wherein the disease is:
Rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis,
Septic shock, pancreatitis, traumatic brain injury, organ transplant rejection, osteoarthritis, asthma,
The method, which is psoriasis or Alzheimer's disease. 18. A method for inhibiting ICE-mediated function in a patient, comprising administering the compound according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 to the patient. Administering to the subject. 19. A method for reducing the production of IGIF or IFN-γ in a patient, comprising the compound according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15. Administering to the patient. 20. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 in the manufacture of a medicament for treating or preventing a disease. Wherein the disease is the following disease in a patient: IL-1 mediated disease, apoptosis mediated disease, inflammatory disease, autoimmune disease, destructive bone disorder, proliferative disorder, infectious disease, degenerative disease, necrosis Sexual disorders, excessive food alcohol use disorders, viral borne diseases, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma,
Adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, Autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, graft-versus-host disease, osteoporosis, multiple myeloma-related bone disorders, acute Myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, bacillary dysentery, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal atrophy , Multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia,
Use, which is a disease selected from seizure neurological damage, ulcerative colitis, traumatic brain injury, organ transplant rejection, hepatitis B, hepatitis C, hepatitis G, yellow fever, dengue or Japanese encephalitis. . 21. The use according to claim 20, wherein said disease is:
Rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis,
Septic shock, pancreatitis, traumatic brain injury, organ transplant rejection, osteoarthritis, asthma,
Use which is psoriasis or Alzheimer's disease. 22. The use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 in the manufacture of a medicament for inhibiting ICE-mediated function in a patient. The use wherein the use comprises administering to the patient a compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15. 23. A compound according to any one of claims 1 to 14, or a pharmaceutical agent according to claim 15, in the manufacture of a medicament for reducing the production of IGIF or IFN-γ in a patient. Use of a composition, comprising administering to the patient a compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15.